tacrolimus and Candidiasis

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

Inverse psoriasis is clinically defined by chronic inflammatory lesions in intertrigineous areas. Colonisation or infection with Candida ssp. or bacteria is common. The disease-related quality of life is significantly reduced especially regarding sexual behavior. After the exclusion of relevant differential diagnoses, therapy should be adapted to the clinical outcome and potential comorbidities. Substances which are efficacious in psoriasis vulgaris are generally efficacious in inverse psoriasis, but have to be used off-label. Controlled clinical studies are only available for topical ascomycin.

Topics: Bacterial Infections; Candidiasis; Diagnosis, Differential; Female; Humans; Male; Off-Label Use; Psoriasis; Superinfection; Tacrolimus

Recent studies have established the pivotal role of irritants and allergens in development of chronic paronychia and the significant improvement with corticosteroid therapy.. The objective of this randomized, unblinded, comparative study was to compare the efficacy of tacrolimus ointment 0.1% vs. betamethasone 17-valerate 0.1% in the treatment of chronic paronychia.. Forty-five patients with chronic paronychia were randomized 1:1:1 to apply twice daily either betamethasone 17-valerate 0.1% or tacrolimus 0.1% ointment or emollient. Protective measures were counselled to all patients. Treatment duration was 3 weeks and patients were followed for an additional 6 weeks.. Eight patients in the betamethasone group were considered as cured, two as improved and four as nonresponders at the end of the treatment period. Thirteen patients in the tacrolimus group were considered as cured and one as improved at the end of the treatment period. Nine patients in the emollient group were considered as stable and six failed to respond. Both betamethasone and tacrolimus groups presented statistically significantly greater cure or improvement rates when compared with the emollient group (P<0.001).. Tacrolimus ointment appears to be a more efficacious agent than betamethasone 17-valerate or placebo for the treatment of chronic paronychia.

Topics: Betamethasone Valerate; Candidiasis; Chronic Disease; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Paronychia; Tacrolimus; Treatment Outcome

Topics: Antifungal Agents; Calcineurin Inhibitors; Candida; Candidiasis; Cyclosporine; Drug Synergism; Humans; Immunosuppressive Agents; Microbial Sensitivity Tests; Tacrolimus

Topics: Antifungal Agents; Antineoplastic Agents; Candidiasis; Carcinoma; Esophageal Neoplasms; Female; Humans; Immunosuppression Therapy; Kidney Transplantation; Middle Aged; Recurrence; Tacrolimus; Treatment Outcome

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

Biofilms produced by Candida albicans (C. albicans) are intrinsically resistant to fungicidal agents, which are a main cause of the pathogenesis of catheter infections. Several lines of evidence have demonstrated that calcineurin inhibitor FK506 or cyclosporine A (CsA) can remarkably enhance the antifungal activity of fluconazole (FLC) against biofilm-producing C. albicans strain infections. The aim of present study is thus to interrogate the mechanism underpinning the synergistic effect of FLC and calcineurin inhibitors.. Twenty four clinical C. albicans strains isolated from bloodstream showed a distinct capacity of biofilm formation. A combination of calcineurin inhibitor CsA and FLC exhibited a dose-dependent synergistic antifungal effect on the growth and biofilm formation of C. albicans isolates as determined by a XTT assay and fluorescent microscopy assay. The synergistic effect was accompanied with a significantly down-regulated expression of adhesion-related genes ALS3, hypha-related genes HWP1, ABC transporter drug-resistant genes CDR1 and MDR1, and FLC targeting gene, encoding sterol 14alpha-demethylase (ERG11) in clinical C. albicans isolates. Furthermore, an addition of CsA significantly reduced the cellular surface hydrophobicity but increased intracellular calcium concentration as determined by a flow cytometry assay (p < 0.05).. The results presented in this report demonstrated that the synergistic effect of CsA and FLC on inhibited C. albicans biofilm formation and enhanced susceptibility to FLC was in part through a mechanism involved in suppressing the expression of biofilm related and drug-resistant genes, and reducing cellular surface hydrophobicity, as well as evoking intracellular calcium concentration.

Topics: Antifungal Agents; Biofilms; Calcineurin Inhibitors; Candida albicans; Candidiasis; Cyclosporine; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Fungal; Drug Synergism; Fluconazole; Humans; Microbial Sensitivity Tests; Tacrolimus

Topics: Antifungal Agents; Calcineurin; Calcium Channels; Candida albicans; Candidiasis; Cyclosporins; Drug Resistance, Fungal; Fungal Proteins; HSP90 Heat-Shock Proteins; Humans; Signal Transduction; Tacrolimus

Topics: Antifungal Agents; Biofilms; Candida albicans; Candidiasis; Cyclosporine; Drug Resistance, Fungal; Drug Therapy, Combination; Humans; Tacrolimus

Thrombotic microangiopathy (TMA) is a rare complication associated with the use of calcineurin inhibitors in lung transplantation, irrespective of the underlying disease of the graft recipient. It usually occurs in incomplete forms, complicating and delaying diagnosis until damage is already irreversible. It is unrelated to time from transplantation and often presents with concomitant infection, which tends to confound diagnosis. The cases discussed here have a common causative agent and all present with concomitant infection. Treatment recommendations have changed in recent years with the introduction of plasmapheresis or, more recently, the availability of the antibody eculizumab. Notwithstanding, the most cost-effective measure is withdrawal or switching of the calcineurin inhibitor. TMA is an underdiagnosed clinical entity that should be considered in the management of transplantation patients.

Topics: Abscess; Candida glabrata; Candidiasis; Creatinine; Disease Susceptibility; Drug Substitution; Erythrocytes, Abnormal; Everolimus; Female; Hemoglobins; Humans; Immunosuppressive Agents; L-Lactate Dehydrogenase; Lung Transplantation; Male; Middle Aged; Myositis; Nocardia Infections; Platelet Transfusion; Pneumonia; Postoperative Complications; Tacrolimus; Thrombotic Microangiopathies; Young Adult

In vitro interaction between tacrolimus (FK506) and four azoles (fluconazole, ketoconazole, itraconazole and voriconazole) against thirty clinical isolates of both fluconazole susceptible and -resistant Candida glabrata were evaluated by the checkerboard microdilution method. Synergistic, indifferent or antagonism interactions were found for combinations of the antifungal agents and FK506. A larger synergistic effect was observed for the combinations of FK506 with itraconazole and voriconazole (43%), followed by that of the combination with ketoconazole (37%), against fluconazole-susceptible isolates. For fluconazole-resistant C. glabrata , a higher synergistic effect was obtained from FK506 combined with ketoconazole (77%), itraconazole (73%), voriconazole (63%) and fluconazole (60%). The synergisms that we observed in vitro , notably against fluconazole-resistant C. glabrata isolates, are promising and warrant further analysis of their applications in experimental in vivo studies.

Topics: Antifungal Agents; Azoles; Candida glabrata; Candidiasis; Drug Resistance, Bacterial; Drug Synergism; Humans; Microbial Sensitivity Tests; Tacrolimus

Candida krusei is an important agent of opportunistic infections that often displays resistance to several antifungals. We describe here the in vivo acquisition of resistance to voriconazole (VRC) by C. krusei isolates recovered from a leukemia patient during a long period of VRC therapy. In order to mimic the in vivo development of VRC resistance, a susceptible C. krusei isolate was exposed daily to 1 μg/ml of VRC in vitro. Interestingly, after 5 days of exposure to VRC, a MIC of 4 μg/ml was achieved; this value remained constant after 25 additional days of treatment with VRC and also after 30 consecutive days of incubation in VRC-free medium. Our objective was to determine the associated molecular resistance mechanisms, such as expression of efflux pump genes and ERG11 gene mutations, among the resistant strains. Synergistic effects between the efflux blocker tacrolimus (FK506) and VRC were found in all of the resistant strains. Moreover, ABC1 gene expression increased over time in both the in vivo- and in vitro-induced resistant strains, in contrast to the ABC2 and ERG11 genes, whose expression was invariably lower and constant. ERG11 gene sequencing showed two different types of mutations, i.e., heterozygosity at T1389T/C, corresponding to synonymous mutations, in C. krusei strains and a missense mutation at position T418C, resulting in a change from Tyr to His, among resistant C. krusei clinical isolates. This study highlights the relevance of ATP-dependent efflux pump (namely, Abc1p) activity in VRC resistance and describes new mutations in the ERG11 gene among resistant C. krusei clinical isolates.

Topics: Adult; Antifungal Agents; Antineoplastic Agents; ATP-Binding Cassette Transporters; Candida; Candidiasis; Drug Resistance, Fungal; Fluconazole; Fungal Proteins; Gene Expression; Humans; Male; Mutation; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sterol 14-Demethylase; Tacrolimus; Voriconazole

The object of this study was to test whether posaconazole, a broad-spectrum antifungal agent inhibiting ergosterol biosynthesis, exhibits synergy with the β-1,3 glucan synthase inhibitor caspofungin or the calcineurin inhibitor FK506 against the human fungal pathogen Candida albicans. Although current drug treatments for Candida infection are often efficacious, the available antifungal armamentarium may not be keeping pace with the increasing incidence of drug resistant strains. The development of drug combinations or novel antifungal drugs to address emerging drug resistance is therefore of general importance. Combination drug therapies are employed to treat patients with HIV, cancer, or tuberculosis, and has considerable promise in the treatment of fungal infections like cryptococcal meningitis and C. albicans infections. Our studies reported here demonstrate that posaconazole exhibits in vitro synergy with caspofungin or FK506 against drug susceptible or resistant C. albicans strains. Furthermore, these combinations also show in vivo synergy against C. albicans strain SC5314 and its derived echinocandin-resistant mutants, which harbor an S645Y mutation in the CaFks1 β-1,3 glucan synthase drug target, suggesting potential therapeutic applicability for these combinations in the future.

Topics: Animals; Antifungal Agents; Base Sequence; Candida albicans; Candidiasis; Caspofungin; Drug Resistance, Fungal; Drug Synergism; Echinocandins; Ergosterol; Lipopeptides; Male; Mice; Molecular Sequence Data; Mutation; Sequence Homology, Nucleic Acid; Tacrolimus; Triazoles

Most Candida krusei strains are innately resistant to fluconazole (FLC) and can cause breakthrough candidemia in immunocompromised individuals receiving long-term prophylactic FLC treatment. Although the azole drug target, Erg11p, of C. krusei has a relatively low affinity for FLC, drug efflux pumps are also believed to be involved in its innate FLC resistance. We describe here the isolation and characterization of Abc1p, a constitutively expressed multidrug efflux pump, and investigate ERG11 and ABC1 expression in C. krusei. Examination of the ERG11 promoter revealed a conserved azole responsive element that has been shown to be necessary for the transcription factor Upc2p mediated upregulation by azoles in related yeast. Extensive cloning and sequencing identified three distinct ERG11 alleles in one of two C. krusei strains. Functional overexpression of ERG11 and ABC1 in Saccharomyces cerevisiae conferred high levels of resistance to azoles and a range of unrelated Abc1p pump substrates, while small molecule inhibitors of Abc1p chemosensitized C. krusei to azole antifungals. Our data show that despite the presence of multiple alleles of ERG11 in some, likely aneuploid, C. krusei strains, it is mainly the low affinity of Erg11p for FLC, together with the constitutive but low level of expression of the multidrug efflux pump Abc1p, that are responsible for the innate FLC resistance of C. krusei.

Topics: Amino Acid Sequence; Animals; Antifungal Agents; ATP-Binding Cassette Transporters; Azoles; Blotting, Northern; Blotting, Southern; Candida; Candidiasis; Cell Membrane; Chromosomes, Fungal; Drug Resistance, Fungal; Endoplasmic Reticulum; Humans; Phenotype; Plasmids; Reverse Transcriptase Polymerase Chain Reaction; Saccharomyces cerevisiae

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

Several mechanisms may be associated with Candida albicans resistance to azoles. Ibuprofen was described as being able to revert resistance related to efflux activity in Candida. The aim of this study was to uncover the molecular base of antifungal resistance in C. albicans clinical strains that could be reverted by ibuprofen. Sixty-two clinical isolates and five control strains of C. albicans were studied: the azole susceptibility phenotype was determined according to the Clinical Laboratory for Standards Institute, M27-A2 protocol and minimal inhibitory concentration values were recalculated with ibuprofen (100 microg mL(-1)); synergistic studies between fluconazole and FK506, a Cdr1p inhibitor, were performed using an agar disk diffusion assay and were compared with ibuprofen results. Gene expression was quantified by real-time PCR, with and without ibuprofen, regarding CDR1, CDR2, MDR1, encoding for efflux pumps, and ERG11, encoding for azole target protein. A correlation between susceptibility phenotype and resistance gene expression profiles was determined. Ibuprofen and FK506 showed a clear synergistic effect when combined with fluconazole. Resistant isolates reverting to susceptible after incubation with ibuprofen showed CDR1 and CDR2 overexpression especially of the latter. Conversely, strains that did not revert displayed a remarkable increase in ERG11 expression along with CDR genes. Ibuprofen did not alter resistance gene expression significantly (P>0.05), probably acting as a Cdrp blocker.

Topics: Antifungal Agents; Azoles; Candida albicans; Candidiasis; Drug Resistance, Fungal; Drug Synergism; Enzyme Inhibitors; Fluconazole; Fungal Proteins; Gene Expression Profiling; Humans; Ibuprofen; Membrane Transport Proteins; Microbial Sensitivity Tests; Tacrolimus

Infection is a common cause of morbidity and mortality in kidney transplant recipients. The incidence of esophageal and urogenital candidiasis in kidney and kidney-pancreas transplant recipients has not been well documented. Azoles are safe, effective agents to treat esophageal candidiasis. However, resistance to azoles is now becoming common. This study reports the use of caspofungin for the treatment of azole-resistant esophageal and urogenital candidiasis in kidney transplant recipients.. The incidence of esophageal and urogenital candidiasis was evaluated among 140 kidney transplantations and four combined kidney-pancreas transplants performed over a 2-year period.. Twenty-two patients (15.7%) presented with esophageal candidiasis, while seven patients (5%) showed urogenital candidiasis. Thirteen patients with esophageal candidiasis (59%) and four patients (57%) with urogenital candidiasis did not improve after a week of azole treatment. A regimen of caspofungin was started in these patients, who tolerated the treatment. Urogenital candidiasis recurred in two patients 2 and 3 months after the treatment. One patient with esophageal candidiasis did not improve with caspofungin and was switched to amphotericin B therapy. There were no other recurrences of candidiasis among patients treated with caspofungin for a median follow-up of 8 months.. Renal transplant patients remain at high risk for fungal infections. Although the number of patients was limited, the results of this study indicated that caspofungin is an effective, well-tolerated alternative for difficult-to-treat, azole-resistant candida infections in kidney and pancreas transplant recipients. The high costs of the drug limit the use of caspofungin as first-line antifungal therapy, reserving its use to recipients who had undergone unsuccessful azole therapy.

Topics: Adult; Aged; Antifungal Agents; Candidiasis; Candidiasis, Vulvovaginal; Caspofungin; Cyclosporine; Echinocandins; Esophageal Diseases; Female; Fluconazole; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lipopeptides; Middle Aged; Peptides, Cyclic; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Animals; Antifungal Agents; Azoles; Candida albicans; Candidiasis; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Immunocompromised Host; Immunosuppressive Agents; Opportunistic Infections; Tacrolimus

Topics: Adult; Aged; Antifungal Agents; Candidiasis; Drug Interactions; Erythromycin; Female; Humans; Immunosuppressive Agents; Ketoconazole; Kidney Transplantation; Male; Phenytoin; Postoperative Complications; Rifampin; Tacrolimus

Topics: Adult; Antifungal Agents; Candidiasis; Drug Interactions; Humans; Immunosuppressive Agents; Itraconazole; Kidney Transplantation; Male; Tacrolimus

The microbial origin, timing, risk factors, and outcome of bloodstream infections (bacteremia and fungemia) were prospectively analyzed in 130 consecutive liver transplant recipients receiving tacrolimus-based immunosuppression; median followup was 3 yr. 22% (29/130) of the patients developed 36 episodes of bloodstream infections (0.28 episodes/patient). Bloodstream infections accounted for 36% (36/100) of all major infections. 81% (29/36) of bloodstream infections were due to bacteremia and 19% (7/36) due to fungemia (candidemia 14% and cryptococcemia 5%). Intravascular catheters were the most frequent source and methicillin-resistant Staphylococcus aureus was the most frequent pathogen causing bloodstream infections. 70% of the catheter related and all bacteremias due to intra-abdominal infections occurred < or = 90 d, whereas 75% of the bacteremias due to biliary source occurred > 90 d after transplantation. Length of initial post-transplant intensive care unit stay (p = 0.014) and readmission to the intensive care unit (p = 0.003) were independently significant predictors of bloodstream infections. 40% of the candidemias occurred within 30 d of transplantation and were of unknown portal, whereas the portal in all candidemias occurring > 30 d post-transplant was known (catheter, hepatic abscess, urinary tract). Mortality in patients with bloodstream infections was 52% (15/29) vs. 9% (9/101) in patients without bloodstream infections (p = 0.0001). In conclusion, intravascular catheters (and not intra-abdominal infections) have emerged as the most common source of bloodstream infections, and gram-positive cocci (S. aureus) as the predominant pathogens in bloodstream infections after liver transplantation.

Topics: Abdomen; Adult; Aged; Bacteremia; Biliary Tract; Candidiasis; Catheterization, Peripheral; Critical Care; Cryptococcosis; Equipment Contamination; Female; Follow-Up Studies; Forecasting; Fungemia; Humans; Immunosuppressive Agents; Length of Stay; Liver Abscess; Liver Transplantation; Male; Methicillin Resistance; Middle Aged; Patient Readmission; Prospective Studies; Risk Factors; Staphylococcal Infections; Staphylococcus aureus; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome; Urinary Tract Infections

The effects of the immunosuppressive agents FK506 (tacrolimus) and cyclosporin (CyA) on Candida albicans infection in mice were compared with those of cyclophosphamide. FK506 and CyA did not exacerbate C. albicans infection in mice when the effects were determined on the basis of survival ratio and colony forming units (CFU) in the kidney, although cyclophosphamide (CY) impaired the host defence mechanisms of mice against C. albicans infection. The effects of FK506 and CyA on the body weight of mice, histopathological changes of lymphoid tissues and formation of granulomas in kidney were also studied in comparison with those of CY.

Topics: Animals; Brain; Candidiasis; Cyclophosphamide; Cyclosporine; Granuloma; Immunosuppressive Agents; Kidney Cortex; Lymphoid Tissue; Male; Mice; Mice, Inbred BALB C; Stem Cells; Survival Analysis; Tacrolimus

A retrospective cohort study was conducted to determine the incidence of major infectious complications after orthotopic liver transplantation and to compare outcomes in patients receiving either cyclosporine (CsA) or FK506 (tacrolimus) as primary immunosuppression. Of 133 transplants performed in 118 patients, 124 transplant episodes were evaluated. Cytomegalovirus (CMV) infection (INF) and disease (DIS), deep fungal infection (DFI), and intraabdominal bacterial infections (IAI) were catalogued. The overall incidences of major infectious outcomes were: CMV INF = 33%; CMV DIS = 19%; DFI = 15%; and IAI = 25%. Cox proportional hazard analysis identified donor seropositivity, OKT3 as secondary immunosuppression and initial intensive care unit (ICU) duration as risk factors for CMV INF and DIS in the overall population. Fungal colonization was the dominant risk factor associated with deep fungal infection. A choledochojejunostomy anastomosis, the number of cellular blood products transfused at the time of transplantation surgery, and prior CMV INF were independent risk factors for both fungal colonization and deep infection. The single risk factor identified for intraabdominal bacterial infections was the number of cellular blood products transfused at the time of surgery. In the Cox proportional hazards model the relative risk (RR) for each category of infection was lower in the FK506 group (CMV: RR = .87, 95% confidence interval [C.I.] = [.32-2.4]; DFI: .58 [.13-2.6]; IAI: .51 [.15-1.7]), but the effect was not statistically significant. Survival was similar in patients receiving FK506 or CsA. CMV INF and DFI were independent predictors of death for all patients. Risk factors identified for CMV INF and DIS support the findings of others. Higher intraoperative blood product requirements and complicated intraoperative or postoperative courses increase the risk for IAI or DFI. The development of effective strategies to prevent CMV and fungal infections in liver transplant recipients remains a priority for future endeavors.

Topics: Bacterial Infections; Candidiasis; Cohort Studies; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Humans; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus