tacrolimus and Aspergillosis

Increases in the incidence and mortality due to the major invasive fungal infections such as aspergillosis, candidiasis and cryptococcosis caused by the species of Aspergillus, Candida and Cryptococcus, are a growing threat to the immunosuppressed patient population. In addition to the limited armamentarium of the current classes of antifungal agents available (pyrimidine analogs, polyenes, azoles, and echinocandins), their toxicity, efficacy and the emergence of resistance are major bottlenecks limiting successful patient outcomes. Although these drugs target distinct fungal pathways, there is an urgent need to develop new antifungals that are more efficacious, fungal-specific, with reduced or no toxicity and simultaneously do not induce resistance. Here we review several lines of evidence which indicate that the calcineurin signaling pathway, a target of the immunosuppressive drugs FK506 and cyclosporine A, orchestrates growth, virulence and drug resistance in a variety of fungal pathogens and can be exploited for novel antifungal drug development.

Topics: Antifungal Agents; Aspergillosis; Calcineurin; Calcineurin Inhibitors; Candida albicans; Candidiasis; Cyclosporine; Drug Discovery; Drug Resistance, Fungal; Echinocandins; Fungi; HSP90 Heat-Shock Proteins; Humans; Microbial Sensitivity Tests; Signal Transduction; Tacrolimus; Tacrolimus Binding Protein 1A; Virulence

Patients on immunosuppression are at risk of unusual infections. We present a man diagnosed to have adult-onset Still's disease who, on high-dose oral steroid and tacrolimus, developed a cavitating pneumonia due to co-infection with Aspergillus flavus and Nocardia. Timely diagnosis and institution of appropriate therapy resulted in a favourable clinical outcome. Such co-infection in a patient receiving tacrolimus is rare in the published literature. This case serves to emphasise the need to be vigilant for unusual infections in patients who are immunosuppressed, either due to drugs or underlying disease condition.

Topics: Adult; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Coinfection; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunocompromised Host; Immunosuppressive Agents; Male; Nocardia Infections; Pneumonia; Radiography, Thoracic; Steroids; Still's Disease, Adult-Onset; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Immunosuppressive drugs lead to an enhanced risk for infection. The impact of these drugs on the immune system can be broad (eg, corticosteroids) or targeted (eg, rituximab). Infections can have serious consequences, particularly if there is a delay in diagnosis. It is hoped that a knowledge of the type of immune defects that are induced by these drugs and the specific infections that have been reported will guide clinicians in the appropriate use of prophylactic regimens and diagnostic considerations in the event of pneumonia.

Topics: Aspergillosis; Communicable Diseases; Cyclosporine; Glucocorticoids; Humans; Immunosuppressive Agents; Lung Diseases; Methotrexate; Pneumonia, Pneumocystis; Purine Nucleosides; Tacrolimus; Tuberculosis; Tumor Necrosis Factor-alpha

We assessed predictive factors and characteristics of patients with late-onset invasive aspergillosis in the current era of novel immunosuppressive agents. Forty transplant recipients with invasive aspergillosis were included in this prospective, observational study initiated in 2003 at our institutions. In 50% (20/40) of these patients, the infections were late-occurring. Receipt of sirolimus in conjunction with tacrolimus for refractory rejection or cardiac allograft vasculopathy (P=0.047) was significantly associated with late-onset infection. The use of depleting or non-depleting T or B-cell antibodies, either as induction or as antirejection therapy did not correlate with time to onset of invasive aspergillosis. Mortality at 90 days was 20% (4/20) for the patients with early-onset infection and 45% (9/20) for those with late-onset infection (P=0.17). Thus, nearly one-half of the Aspergillus infections in transplant recipients in the current era are late-occurring. These data have implications relevant for prophylactic strategies and guiding clinical management of transplant recipients presenting with pulmonary infiltrates.

Topics: Adult; Age of Onset; Aged; Antibodies; Antifungal Agents; Aspergillosis; B-Lymphocytes; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Postoperative Complications; Prospective Studies; Risk Factors; Sirolimus; Spain; T-Lymphocytes; Tacrolimus; Treatment Outcome; United States

Topics: Aspergillosis; Cyclosporine; Graft Rejection; Humans; Liver Transplantation; Methylprednisolone; Muromonab-CD3; Retrospective Studies; Risk Factors; Tacrolimus

Isavuconazole has theoretical advantages over other mold-active triazoles for the treatment of invasive aspergillosis and mucormycosis after solid organ transplantation (SOT). The available clinical experience, nevertheless, is scarce.. We performed a retrospective study including all adult SOT recipients with proven or probable invasive mold disease (IMD) that received isavuconazole for ≥24 h as first-line or salvage therapy at 10 Spanish centers between September 2017 and November 2021. The primary efficacy outcome was clinical response (complete or partial resolution of attributable symptoms and findings) by weeks 6 and 12. Safety outcomes included the rates of treatment-emergent adverse events and premature isavuconazole discontinuation.. We included 81 SOT recipients that received isavuconazole for a median of 58.0 days because of invasive aspergillosis (n = 71) or mucormycosis (n = 10). Isavuconazole was used as first-line (72.8%) or salvage therapy due because of previous treatment-emergent toxicity (11.1%) or refractory IMD (7.4%). Combination therapy was common (37.0%), mainly with an echinocandin or liposomal amphotericin B. Clinical response by weeks 6 and 12 was achieved in 53.1% and 54.3% of patients, respectively, and was more likely when isavuconazole was administered as first-line single-agent therapy. At least 1 treatment-emergent adverse event occurred in 17.3% of patients, and 6.2% required premature discontinuation. Daily tacrolimus dose was reduced in two-thirds of patients by a median of 50.0%, although tacrolimus levels remained stable throughout the first month of therapy.. Isavuconazole is a safe therapeutic option for IMD in SOT recipients, with efficacy comparable to other patient groups.

Topics: Adult; Antifungal Agents; Aspergillosis; Fungi; Humans; Invasive Fungal Infections; Mucormycosis; Nitriles; Organ Transplantation; Retrospective Studies; Tacrolimus; Transplant Recipients; Triazoles

Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre- and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F

Topics: Allergens; Animals; Apoptosis; Aspergillosis; Aspergillus; Asthma; Calcium-Binding Proteins; Enteritis; Eosinophilia; Eosinophils; Fibrosis; Gastritis; Humans; Hypersensitivity; Immunosuppressive Agents; Interleukin-13; Interleukin-5; Lung; Mice; Mice, Inbred BALB C; Mice, Transgenic; Muscle Proteins; Respiratory Mucosa; Tacrolimus

Calcineurin is important for fungal virulence and a potential antifungal target, but compounds targeting calcineurin, such as FK506, are immunosuppressive. Here we report the crystal structures of calcineurin catalytic (CnA) and regulatory (CnB) subunits complexed with FK506 and the FK506-binding protein (FKBP12) from human fungal pathogens (Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Coccidioides immitis). Fungal calcineurin complexes are similar to the mammalian complex, but comparison of fungal and human FKBP12 (hFKBP12) reveals conformational differences in the 40s and 80s loops. NMR analysis, molecular dynamic simulations, and mutations of the A. fumigatus CnA/CnB-FK506-FKBP12-complex identify a Phe88 residue, not conserved in hFKBP12, as critical for binding and inhibition of fungal calcineurin. These differences enable us to develop a less immunosuppressive FK506 analog, APX879, with an acetohydrazine substitution of the C22-carbonyl of FK506. APX879 exhibits reduced immunosuppressive activity and retains broad-spectrum antifungal activity and efficacy in a murine model of invasive fungal infection.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Binding Sites; Calcineurin; Calcineurin Inhibitors; Candida albicans; Cells, Cultured; Coccidioides; Cryptococcosis; Cryptococcus neoformans; Crystallography, X-Ray; Drug Discovery; Female; Male; Mice; Mice, Inbred A; Mice, Inbred C57BL; Molecular Dynamics Simulation; Tacrolimus; Tacrolimus Binding Protein 1A

To investigate the expression and roles of type I and II interferons (IFNs) in fungal keratitis, as well as the therapeutic effects of tacrolimus (FK506) and voriconazole on this condition.. After zymosan stimulation of mouse neutrophils, lymphocytes, macrophages, and A6(1) cells, the IFN mRNA and protein expression levels were markedly increased until 24 h, peaking at 8 h (p<0.001). The mRNA and protein expression levels of inflammatory cytokines (IL-1α, IL-6, IL-12, and IL-17) were also upregulated after zymosan stimulation. Moreover, type I (IFN-α/β) and type II (IFN-γ) IFN expression levels were increased and positively correlated with the progression of fungal keratitis in vivo. FK506 administered with voriconazole reduced the pathological infiltration of inflammatory cells into the cornea and downregulated the expression levels of IFNs and related inflammatory cytokines.. In conclusion, this study demonstrated that type I and II IFN levels were markedly increased in fungal keratitis and that FK506 combined with voriconazole decreased the severity of fungal keratitis by suppressing type I and II IFNs and their related inflammatory responses.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cornea; Disease Models, Animal; Drug Combinations; Drug Synergism; Epithelial Cells; Eye Infections, Fungal; Female; Gene Expression Regulation; Interferons; Interleukins; Keratitis; Lymphocytes; Macrophages; Mice; Mice, Inbred C57BL; Neutrophils; Severity of Illness Index; Tacrolimus; Voriconazole; Zymosan

FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-nuclear factor of activated T cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human-pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Calcineurin; Calcineurin Inhibitors; Candida albicans; Candidiasis; Cells, Cultured; Cryptococcosis; Cryptococcus neoformans; Female; Fluconazole; Immunosuppressive Agents; Male; Mice; Microbial Sensitivity Tests; Tacrolimus; Tacrolimus Binding Protein 1A

Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin-NFAT activation is phagocytosis dependent and collaborates with NF-κB for TNF-α production. For yeast zymosan particles, activation of macrophage calcineurin-NFAT occurs via the phagocytic Dectin-1-spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9-dependent and Bruton's tyrosine kinase-dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF-κB for TNF-α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9-BTK-calcineurin-NFAT signalling pathway as a key immune defect that leads to organ transplant-related invasive aspergillosis.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Aspergillosis; Aspergillus fumigatus; Calcineurin; Calcineurin Inhibitors; Cells, Cultured; Disease Models, Animal; Immunity, Innate; Macrophages; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; NFATC Transcription Factors; Phagocytosis; Protein-Tyrosine Kinases; Signal Transduction; Tacrolimus; Toll-Like Receptor 9; Tumor Necrosis Factor-alpha; Zebrafish

Antifungal prophylaxis with liposomal amphotericin B in high-risk liver transplant recipients is recommended, but experience with amphotericin B lipid complex (ABLC, Abelcet(®)) in this setting is limited. Data from 615 liver transplants performed during 1999-2005 were analyzed retrospectively. High-risk patients (n = 146) received a mean cumulative ABLC dose of 955 ± 609 mg (mean duration of 23.3 ± 11.9 days). Low-risk patients (n = 469) received no prophylaxis. During a mean follow-up of 43.8 ± 29.2 months, fungal infections occurred in 32.2% of ABLC patients versus 43.5% of non-prophylaxis patients (P = 0.015). The overall rate of invasive fungal infection was 12.3% in the ABLC group versus 15.6% in the non-prophylaxis patients (P = 0.34). Any Candida infection (ABLC 29.5%, non-prophylaxis 41.2%, P = 0.011), probable or proven invasive Candida infection requiring systemic antifungal treatment (ABLC 18.5%, non-prophylaxis 32.4%, P = 0.001) and invasive abdominal candidiasis during the first 3 months (ABLC 4.1%, non-prophylaxis 9.2%, P = 0.049) were significantly less frequent in the ABLC group. There was no significant difference between groups in the incidence of Aspergillus infections. The ABLC group showed no evidence of nephrotoxicity. In conclusion, the marked and significant differences in infection rates and requirement for systemic treatment in this large population suggest that targeted use of low-dose ABLC therapy to high-risk patients is a valid prophylactic strategy following liver transplantation.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis, Invasive; Cyclosporine; Female; Follow-Up Studies; France; Humans; Immunosuppressive Agents; Kidney; Liposomes; Liver Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Retrospective Studies; Safety; Tacrolimus; Treatment Outcome

Due to the limited number of antifungals and the emergence of resistance, new therapies against invasive aspergillosis are needed. We show that calcineurin inhibitors are active in vitro against both azole- and echinocandin-resistant Aspergillus fumigatus strains. The heat shock protein 90 (Hsp90) inhibitor geldanamycin had modest activity when used alone, but its combination with caspofungin or tacrolimus (FK506) resulted in fungicidal activity against azole-resistant strains. Targeting the Hsp90-calcineurin axis is a promising alternative strategy against azole-resistant A. fumigatus strains.

Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Benzoquinones; Calcineurin Inhibitors; Caspofungin; Drug Resistance, Multiple, Fungal; Drug Therapy, Combination; Echinocandins; HSP90 Heat-Shock Proteins; Lactams, Macrocyclic; Lipopeptides; Microbial Sensitivity Tests; Tacrolimus

To establish polyhexamethylene biguanide (PHMB) as an effective treatment for Aspergillus keratitis in a novel murine model. To determine the ability of the calcineurin inhibitors tacrolimus (FK506) and cyclosporine A (CSA) to enhance the activity of PHMB, amphotericin B (AMB), and voriconazole (VCZ) against Aspergillus keratitis.. Broth antifungal susceptibility tests were performed with PHMB, AMB, VCZ, and FK506, individually and in combination against Aspergillus fumigatus. Minimum inhibitory concentrations (MIC) and fractional inhibitory concentration index (FICI) values were used to analyze antifungal activity. In vivo studies: A novel murine model was created to establish Aspergillus keratitis. Infected mice were randomly assigned to treatment groups receiving saline, CSA, AMB, VCZ, PHMB, AMB+CSA, VCZ+CSA, or PHMB+CSA. An ophthalmologist blinded to the treatment groups assessed disease severity daily based on a grading scale. The mean end change in disease score was compared between groups.. FK506 in combination with PHMB, VCZ, or AMB enhanced fungal growth inhibition. FICI values showed an additive effect between FK506 and PHMB, AMB, or VCZ. PHMB monotherapy eliminated Aspergillus growth starting at 4 μg/mL. In vivo studies: All treatment groups showed a significant improvement in disease score compared to the control group. CSA significantly worsened VCZ activity against Aspergillus keratitis.. PHMB is an effective inhibitor of Aspergillus growth. Further investigation of the role of calcineurin inhibitors in the treatment for Aspergillus keratitis is warranted.

Topics: Amphotericin B; Animals; Aspergillosis; Aspergillus fumigatus; Biguanides; Calcineurin Inhibitors; Corneal Ulcer; Cyclosporine; Disinfectants; Drug Synergism; Eye Infections, Fungal; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Prospective Studies; Pyrimidines; Tacrolimus; Triazoles; Voriconazole

Surfactant protein D (SP-D) plays a central role in pulmonary innate immune responses to microbes and allergens, often enhancing clearance of inhaled material. Although SP-D functions during bacterial and viral infections are well established, much less is known about its possible roles during invasive fungal infections. Aspergillus fumigatus is a prominent fungal pathogen in immunocompromised individuals, and can cause allergic or invasive aspergillosis. SP-D has been shown to be protective against both of these disease modalities. The moieties present on the fungal surface responsible for SP-D binding remain largely unclear, although cell wall 1,3-beta-D-glucan is bound by SP-D in other fungal species. There is little information regarding the interaction of SP-D with A. fumigatus hyphae which are responsible for the invasive form of disease. Here, we show that SP-D binding to A. fumigatus hyphae is sensitive to the activity of the calcium-activated protein phosphatase calcineurin. Deletion of the catalytic subunit calcineurin A (DeltacnaA) or pharmacologic inhibition of calcineurin through FK506 abrogated SP-D binding. In contrast, SP-D binding to Cruptococcus neoformans was calcineurin-independent. Pharmacologic inhibition of A. fumigatus cell wall components by caspofungin (inhibits 1,3-beta-D-glucan synthesis) and nikkomycin Z (inhibits chitin synthesis) increased SP-D binding to the wild-type strain. In contrast, SP-D binding increased in the DeltacnaA strain only after nikkomycin Z treatment. We conclude that SP-D binding to A. fumigatus hyphae is calcineurin-sensitive, presumably as a consequence of calcineurin's role in regulating production of key cell wall binding partners, such as 1,3-beta-D-glucan. Elucidation of the interaction between lung innate immune factors and A. fumigatus could lead to the development of novel therapeutic interventions.

Topics: Aminoglycosides; Animals; Aspergillosis; Aspergillus fumigatus; Calcineurin; CHO Cells; Cricetinae; Cricetulus; Cryptococcus neoformans; Flow Cytometry; Humans; Hyphae; Lung; Pulmonary Surfactant-Associated Protein D; Tacrolimus

Aspergillosis is a high-risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug-drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels.. VRZ TDM data analysis for trough concentration (C0) and peak concentration (C2) was carried out, using validated liquid chromatography assay with ultraviolet detection, for 35 CF lung transplant patients (mean age 25 years, mean weight 47 kg, balanced sex ratio) since 2003. Therapeutic range (C0: 1.5 +/- 0.5 - C2 : 4.0 +/- 1.0 mg/L) was expressed relative to pivotal pharmacokinetic trial data.. The duration of VRZ treatment ranged from 9 days to 22 months. The recommended standard dose of VRZ (200 mg twice a day, following the loading dose) resulted in significant plasma concentrations (>0.5 mg/L) in 20% of CF lung transplant patients. Therapeutic concentrations were obtained using higher doses (average 570 +/- 160 mg/day, +43%, P<0.01). Despite adaptation, C0 remained <0.5 mg/L (11%), even when the drug was administered intravenously, highlighting the variability of VRZ pharmacokinetics, possibly enhanced by CYP2C19 polymorphism. The risk of inefficacy during periods of underdosage was overcome by treatment with antifungal drug combinations (caspofungin, n=10). The therapeutic index was limited by neurologic effects (14%) and hepatic abnormalities (30%). VRZ concentrations correlated significantly (P<0.01) with aspartate aminotransferase levels but not with bilirubin levels. VRZ acted as a metabolic inhibitor of tacrolimus (C0 to dose ratio 5.8 +/- 2.6, n=31/VRZ versus 1.7 +/- 0.9 alone, P<0.001). Large changes in azole concentration affected the magnitude of the drug-drug interactions and adjustment requirements.. TDM is required because VRZ levels are often undetectable in treated CF lung transplant patients, supporting the use of antifungal drug combinations until achievement of VRZ C0 at a steady state between 1 and 2 mg/L. Plasma VRZ concentrations should be determined for the quantitative, individualized management of drug-drug interactions in lung transplant patients, in particular immunosuppressant such as tacrolimus, considering VRZ to be both a target and an inhibitor of CYP3A4.

Topics: Adolescent; Adult; Antifungal Agents; Aspergillosis; Aspergillus; Cystic Fibrosis; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Mycoses; Pyrimidines; Scedosporium; Tacrolimus; Triazoles; Voriconazole; Young Adult

Oral posaconazole (PSZ), an azole antifungal drug, was recently introduced for the treatment of invasive fungal infections. The prescription of PSZ together with the immunosuppressant tacrolimus (TRL) was evaluated in 14 lung transplant patients with cystic fibrosis. PSZ inhibited CYP3A4 TRL metabolism, resulting in a decrease of TRL dose by a factor of 3, with tapering to a mean of 2 mg/d. Previous studies with itraconazole and voriconazole showed that TRL dose could be decreased by factors of 5 and 4, respectively. Joint therapeutic drug monitoring of TRL and PSZ was carried out to investigate the high risk of interindividual variability associated with this coprescription in such patients.

Topics: Adult; Antifungal Agents; Aspergillosis; Candidiasis; Cystic Fibrosis; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Female; Graft Rejection; Humans; Immunosuppressive Agents; Itraconazole; Lung Transplantation; Male; Microbial Sensitivity Tests; Mycoses; Prescriptions; Pyrimidines; Tacrolimus; Triazoles; Voriconazole

Voriconazole is an anti-fungal agent active against Aspergillus infection that is used for prophylaxis and curative treatment in lung transplant patients. We present nine cases of painful neuromuscular disorders, an unusual and rare side effect of high-dose voriconazole in association with tacrolimus.

Topics: Adolescent; Adult; Aspergillosis; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Lung Transplantation; Male; Middle Aged; Neuromuscular Diseases; Pain; Postoperative Complications; Pyrimidines; Retrospective Studies; Risk Assessment; Severity of Illness Index; Tacrolimus; Treatment Outcome; Triazoles; Voriconazole

We performed in vitro antifungal checkerboard testing on 12 Aspergillus fumigatus clinical isolates (6 transplant recipients and 6 nontransplant patients) with three antifungal agents (amphotericin B, voriconazole, and caspofungin) and three immunosuppressants (FK506, cyclosporine, and rapamycin). We were not able to detect a difference in calcineurin inhibitor antifungal activity against isolates from transplant recipients and nontransplant patients.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Calcineurin Inhibitors; Caspofungin; Cyclosporine; Echinocandins; Humans; Immunosuppressive Agents; Lipopeptides; Organ Transplantation; Peptides, Cyclic; Pyrimidines; Tacrolimus; Triazoles; Voriconazole

Cyclosporin A, tacrolimus, and sirolimus are immunosuppressive agents initially described as antifungal compounds with different activities for Aspergillus species. The outcome of invasive aspergillosis in mice treated with each agent was investigated in outbred CD-1 mice. Immunosuppressant or vehicle alone was administered from days -1 to +14. Mice were infected on day 0 with resting Aspergillus conidia via lateral tail vein injection. Survival was significantly greater with most regimens than for mice treated with cyclosporin A (100 mg/kg/day; median survival, 3 days): tacrolimus, 1 mg/kg/day (6.5 days, P = .003); sirolimus, 1 or 10 mg/kg/day (7.5 and 9.5 days, respectively; P = .002 and .0001); and vehicle alone (6.5 days, P = .001). However, mice treated with 10 mg/kg/day of tacrolimus survived a median of 4.5 days (P = .25). Survival in the 10-mg sirolimus group did not differ from that of mice given vehicle alone (P = .55). Histologic evaluation suggested the improved survival with tacrolimus and sirolimus may be due in part to direct anti-Aspergillus activity.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus; Brain; Cyclosporine; Immunosuppressive Agents; Mice; Polyenes; Sirolimus; Tacrolimus