tacrolimus and posaconazole

Four months after receiving an orthotopic liver transplant, a 51-year-old man was admitted for progressive liver failure and severe hepatocellular necrosis thought to be due to tacrolimus. During his hospitalization he experienced bloodstream infections including fungemia due to Trichosporon mucoides and prolonged undulating fever despite antifungal and antibacterial treatment. He underwent removal of the allograft and implantation of another liver. Fever continued postoperatively until therapy with posaconazole was initiated. Initiation of posaconazole led to clinical improvement until the patient's demise from bacteremic vancomycin-resistant enterococcal peritonitis. Trichosporonosis appears to be an emerging fungal infection among immunocompromised individuals (including both hematological and solid organ transplant recipients). T. mucoides is a rare cause of systemic infection. When it occurs, trichosporonosis usually is associated with hematological malignancies and, to the best of our knowledge, has not been previously reported in a liver transplant recipient. The optimal treatment is not well defined. We report here the first case using posaconazole for treatment of trichosporonosis in a liver transplant recipient caused by T. mucoides.

Topics: Antifungal Agents; Enterococcus faecium; Fatal Outcome; Fungemia; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycoses; Peritonitis; Postoperative Complications; Tacrolimus; Triazoles; Trichosporon; Vancomycin; Vancomycin Resistance

Antifungal prophylaxis is shown to decrease the risk of invasive fungal infection (IFI) after hematopoietic stem-cell transplantation (HSCT). Posaconazole has been approved for prophylaxis in HSCT. However, it is only available orally given three times per day. We evaluated once weekly intravenous amphotericin B lipid complex (ABLC), given its broad-spectrum antifungal activity and prolonged half-life (172 hr), as an alternative prophylaxis in HSCT.. We prospectively randomized allogeneic HSCT patients to receive 7.5 mg/kg of intravenous ABLC weekly or 200 mg of posaconazole orally three times per day as prophylaxis for up to 6 weeks. Endpoints were the incidence of IFI and drug-related toxicities. ABLC was discontinued if creatinine level increased to two times the baseline or greater.. A total of 46 patients were randomized; 40 received at least one dose of the drug and were included in the analysis: 19 received ABLC and 21 received posaconazole. All patients received tacrolimus. Apache II score, neutropenia, and creatinine, bilirubin, and alanine aminotransferase levels were similar in both groups at baseline. One patient in the ABLC arm and none in posaconazole arm developed IFI (5% vs. 0%, P=0.48). More patients in the ABLC arm doubled their serum creatinine (53% vs. 5%, P=0.001) necessitating discontinuation of the study drug.. High-dose prophylactic ABLC in HSCT was associated with nephrotoxicity that could be aggravated by the concomitant use of other nephrotoxic agents. Further studies are needed to evaluate the role of weekly high-dose ABLC as antifungal prophylaxis in patients at lower risk for nephrotoxicity.

Topics: Administration, Oral; Adult; Aged; Amphotericin B; Antifungal Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Leukemia; Lipids; Lymphoma; Male; Middle Aged; Mycoses; Prospective Studies; Risk; Tacrolimus; Time Factors; Transplantation, Homologous; Triazoles

Posaconazole is a broad-spectrum triazole antifungal available as an oral suspension. Pharmacokinetic data showed a high variability of plasma posaconazole concentrations (PPCs) in patients, suggesting a potential interest in drug monitoring. The aim of our prospective study was to measure the PPCs in prophylactically treated patients to evaluate the impact of different factors on these concentrations. In 40 patients treated prophylactically with posaconazole for acute myeloid leukemia or myelodysplastic syndrome between February 2009 and August 2010, PPCs were measured at day 7 of treatment and then twice weekly. Demographic data, clinical data (including gastrointestinal disorders, comedications, and treatment compliance), caloric and fat intake, and biological data were collected and evaluated. We obtained 275 measurements of PPCs, with a median of 430 ng/ml. PPCs were significantly lower in patients with mucositis (P < 0.001), nausea (P = 0.03), diarrhea (P = 0.03), or vomiting (P = 0.05). PPCs were higher in patients with a higher caloric intake (P = 0.02), while the proportion of fat intake had no influence on PPCs (P = 0.84). The concomitant use of proton pump inhibitors decreased the PPCs (P = 0.02), while the use of tacrolimus increased the PPC (P = 0.03). In the multivariate analysis, the factors influencing the PPCs independently were the concomitant use of tacrolimus (P < 0.001), the presence of mucositis (P = 0.01), and food intake (P = 0.02). Our study confirmed the high variability of posaconazole bioavailability and showed the significant influence of gastrointestinal disorders, food intake, and concomitant medication on the PPCs. However, the optimal PPCs still remain to be defined and correlated with clinical efficacy.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Biological Availability; Chromatography, High Pressure Liquid; Drug Monitoring; Female; Food-Drug Interactions; Gastrointestinal Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Multivariate Analysis; Myelodysplastic Syndromes; Prospective Studies; Spectrophotometry, Ultraviolet; Tacrolimus; Triazoles; Young Adult

To analyze the pharmacokinetic properties of the immunosuppressants cyclosporine and tacrolimus when either is coadministered with oral posaconazole.. Two single-center, open-label pharmacokinetic studies of cyclosporine in a multiple-dose design and of tacrolimus in a one-sequence, crossover, single- and multiple-dose design.. One clinical investigative center in the United States and one in the United Kingdom.. Four adult heart transplant recipients in the cyclosporine study and 36 healthy adult volunteers in the tacrolimus study.. In the cyclosporine study, patients who took an established cyclosporine dose 3 times/day for 6 weeks or longer were given posaconazole 200 mg/day for 10 days. In the tacrolimus study, subjects received tacrolimus 0.05 mg/kg/day on days 1 and 14 and posaconazole 400 mg twice/day on days 7-14.. In the cyclosporine study, blood samples were collected on day 1 to determine cyclosporine pharmacokinetics and on day 10 to measure the pharmacokinetics of cyclosporine and posaconazole. Coadministration of posaconazole increased cyclosporine exposure and necessitated dosage reductions of 14-29% for cyclosporine in three subjects. In the tacrolimus study, blood samples were collected on days 12-14 to assess posaconazole pharmacokinetics and on days 1 and 14 for as long 72 hours after dosing to evaluate tacrolimus pharmacokinetics. Posaconazole increased the maximum blood concentration and the area under the concentration-time curve for tacrolimus by 121% and 358%, respectively, on day 14 compared with day 1 (both p=0.001). In both studies, posaconazole pharmacokinetics were unaffected.. These findings suggest that the dosage of cyclosporine or tacrolimus should be reduced when posaconazole therapy is started and that plasma levels of the immunosuppressant should be monitored during and at the discontinuation of posaconazole therapy so that dosages are adjusted accordingly. This recommendation is consistent with current standard of care for patients receiving cyclosporine or tacrolimus with concomitant azole antifungal therapy.

Topics: Adult; Antifungal Agents; Area Under Curve; Cross-Over Studies; Cyclosporine; Drug Interactions; Drug Monitoring; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Triazoles

Limited evidence exists on the effect of isavuconazonium sulfate and posaconazole delayed release tablets on tacrolimus dose-to-concentration ratios in lung transplant recipients.. The purpose of this evaluation was to assess the impact of novel triazoles on tacrolimus dose-to-concentration ratios.. This retrospective review included lung transplant recipient ≥18 years of age from January 1, 2017 to October 1, 2020 who received either posaconazole delayed release tablets or isavuconazonium sulfate for. A paired analysis evaluated outcomes pre-triazole and post-triazole initiation.. Forty-one patients met evaluation criteria for inclusion. A total of 34 of 41 patients received posaconazole delayed release tablets. Of these patients, 22 of 34 were transitioned from previous triazole to posaconazole delayed release tablets and experienced a 47% reduction in tacrolimus dose-to-concentration ratio. Twelve patients were newly initiated on posaconazole delayed release tablets and experienced a 50% reduction in tacrolimus dose-to-concentration ratios. Although not statistically significant, a 30% reduction in tacrolimus dose-to-concentration ratio was observed when transitioning to isavuconazonium sulfate from previous triazole therapy.. Limited data exists to provide guidance on tacrolimus dose adjustments with initiation and conversion of novel triazoles, however, this evaluation provides more knowledge on the drug interaction with novel triazoles and tacrolimus.

Topics: Antifungal Agents; Humans; Tablets; Tacrolimus; Triazoles

Calcineurin inhibitors are commonly used in hematopoietic stem cell transplant (HSCT) patients to prevent graft versus host disease, but as CYP3A4 substrates they are frequently involved in drug-drug interactions. The purpose of this study is to characterize the effects of isavuconazole, fluconazole, and posaconazole on tacrolimus and cyclosporine serum concentrations and dose adjustments in allogeneic HSCT patients.. This retrospective study included patients admitted to Oregon Health and Science University between April 2008 and December 2018 who underwent hematopoietic stem cell transplantation and received concomitant tacrolimus or cyclosporine and fluconazole, isavuconazole or posaconazole therapy. Data on patient characteristics, drug dosing, and serum drug concentrations were collected through chart review, and descriptive statistics were used to summarize the results.. A total of 139 patients were included in this study. We found fluconazole initiation leads to a 25% reduction in both tacrolimus and cyclosporine doses in order to maintain goal serum concentrations. Posaconazole and isavuconazole initiation requires tacrolimus dose reductions by 53% and 21%, respectively.. Based on our experience, FLC, POS, and ISA initiation may require CNI dose reductions and close monitoring of CNI levels to ensure levels remain within goal serum concentrations. Larger studies are needed to fully quantify the percentage in CNI dose reductions and characterize differences among these antifungals.

Topics: Antifungal Agents; Cyclosporine; Fluconazole; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Nitriles; Pyridines; Retrospective Studies; Tacrolimus; Triazoles

A paucity of data currently exists regarding drug-drug interaction (DDI) with tacrolimus and isavuconazole coadministration. Current literature provides conflicting recommendations on whether an empiric tacrolimus dose reduction is necessary when coadministered with isavuconazole. A 47-year-old African American female with acute lymphoblastic leukemia underwent an allogenic stem cell transplant (alloSCT) and was subsequently placed on routine posttransplant therapy including tacrolimus for immunosuppression and posaconazole for antifungal prophylaxis. Tacrolimus was empirically dose reduced due to the expected DDI with posaconazole based on current recommendations. Due to a persistently prolonged QTc interval and need for mold coverage, antifungal prophylaxis was ultimately changed to isavuconazole at standard recommended dosing. Tacrolimus was empirically dose reduced by 40% based on limited available literature at the time; however, tacrolimus trough concentrations subsequently declined, requiring an increase in tacrolimus dose to maintain therapeutic trough concentrations. Adequate isavuconazole absorption was documented through pharmacokinetic and pharmacodynamic data by measuring an isavuconazole trough concentration and directly observing isavuconazole's shortening effect on the QTc interval, respectively. Our experience in an alloSCT patient suggests that an empiric tacrolimus dose reduction is not required when isavuconazole is initiated, but close tacrolimus therapeutic drug monitoring should rather be performed to guide tacrolimus dosing.

Topics: Allografts; Antifungal Agents; Drug Interactions; Drug Monitoring; Drug Tapering; Female; Humans; Immunosuppressive Agents; Middle Aged; Nitriles; Pyridines; Tacrolimus; Triazoles

Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited.. The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant.. This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included.. Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d;. This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.

Topics: Adult; Antifungal Agents; Drug Administration Schedule; Drug Interactions; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Stem Cell Transplantation; Tacrolimus; Triazoles

Topics: Antifungal Agents; Biofilms; Calcineurin Inhibitors; Candida parapsilosis; Drug Synergism; Exophiala; Humans; Itraconazole; Microbial Sensitivity Tests; Phaeohyphomycosis; Tacrolimus; Triazoles; Voriconazole

Administration of azole antifungals to tacrolimus-treated solid organ recipients results in a major drug-drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co-treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose-corrected trough concentrations (C/D) between baseline and tacrolimus-azole co-therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0-20.2) for voriconazole and 4.4 ± 2.6 (range 0.9-18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: -43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (-14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus-azole interaction, but these did not permit accurate predictions in individual patients.

Topics: Antifungal Agents; Biomarkers; Cytochrome P-450 CYP3A; Drug Interactions; Female; Follow-Up Studies; Genotype; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Polymorphism, Single Nucleotide; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Triazoles; Voriconazole

Fungal infection is a common cause of mortality and morbidity in lung transplant recipients (LuTR). Treatment failure to first-line antifungals because of resistance or intolerance is an increasing problem. Posaconazole (PCZ), a triazole antifungal, is an attractive treatment option.. We performed a single-center retrospective study to describe the use, tolerability, efficacy, and drug interaction effect (with tacrolimus) of PCZ oral suspension in LuTR.. Seventy-eight patients were treated with PCZ oral suspension for prophylaxis (n = 15), pre-emptive treatment (n = 31), and treatment of possible (n = 7) and probable (n = 25) invasive fungal infection. A range of fungal isolates was encountered. Resolution was observed in 52.4% (probable, possible, and pre-emptive treatment groups). Aggregate all-cause 1-year mortality was 12.8%. PCZ was well tolerated with 11.5% of patients experiencing adverse effects. Despite dose adjustment strategies, 11.7% of patients experienced supratherapeutic tacrolimus levels, which in 5 cases was associated with a rise (mean 21.6 μmol/L) in serum creatinine.. PCZ is well tolerated and appears effective in the management of fungal infection after lung transplantation. Patients receiving concurrent tacrolimus require careful therapeutic drug monitoring.

Topics: Administration, Oral; Adult; Antifungal Agents; Drug Interactions; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Mycoses; Tacrolimus; Triazoles; Young Adult

Allogeneic hematopoietic stem cell transplant patients are at risk of invasive fungal infections and prophylaxis with azole agents is common practice. The concomitant use of these agents with sirolimus and tacrolimus for the prevention of graft-versus-host disease may result in excessive immunosuppression or toxicity.. This retrospective study identified hospitalized patients who underwent allogeneic hematopoietic stem cell transplantation between August 2009 and April 2011 at Rush University Medical Center. From this group, patients who underwent concomitant tacrolimus, sirolimus, and azole therapy were included for evaluation. The immunosuppression dosing in conjunction with azole use at discharge was analyzed to develop a dosing algorithm dependent on whether fluconazole, posaconazole, or voriconazole was used.. A total of 36 patients were screened for inclusion, of which 8 were excluded due to acute renal failure and/or hemolysis. The remaining patients were stratified by the azole they were concomitantly taking with tacrolimus and sirolimus. The fluconazole arm required the lowest magnitude of dose reductions, while voriconazole required the greatest.. Dose reductions of 50-75% for both sirolimus and tacrolimus, in combination with standard dosing of azole antifungal agents, were necessary to achieve therapeutic drug concentrations for immunosuppressants and potentially avoid toxicities.

Topics: Adult; Aged; Algorithms; Antifungal Agents; Azoles; Drug Dosage Calculations; Female; Fluconazole; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycoses; Retrospective Studies; Sirolimus; Tacrolimus; Triazoles; Voriconazole; Young Adult

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

The calcineurin pathway regulates antifungal drug resistance and the virulence of several major human-pathogenic fungi, including the recalcitrant Mucorales. We hypothesized that the fungistatic triazoles posaconazole (PCZ) and itraconazole (ICZ) become fungicidal in the setting of the calcineurin inhibitor tacrolimus (TCR) and that such an effect is mediated through apoptosis. Fungicidal activity and apoptosis were studied using standard microbiological techniques and hyphal metabolic and vital dye reduction assays at 37°C in RPMI 1640. Apoptosis was characterized by detecting intracellular Ca(2+), phosphatidylserine (PS) externalization, DNA fragmentation, plasma membrane integrity, chromatin condensation, reactive oxygen species (ROS) generation, caspase-like activity, ATP, and cytochrome c release. MICs for PCZ and ICZ alone were significantly higher (8 to 128 μg/ml) than those of PCZ or ICZ plus TCR (0.25 to 4 μg/ml) for Rhizopus oryzae, Cunninghamella bertholletiae, and Mucor circinelloides. Both PCZ and ICZ in combination with TCR became fungicidal, and their activity was mediated through increased apoptotic cell death of R. oryzae (10 to 50%), C. bertholletiae (5 to 50%), and M. circinelloides (5 to 55%) germlings, with morphological apoptotic changes characterized by externalization of PS, nuclear condensation, and DNA fragmentation. Moreover, activation of the caspase-like activity was correlated with cell death induced by TCR plus PCZ or ICZ. These changes correlated with elevated intracellular Ca(2+) and ROS levels and disturbance of mitochondrial potential. We found that PCZ or ICZ in combination with TCR renders Mucorales sensitive to triazoles via apoptotic death. These observations could serve as a new paradigm for the development of new therapeutic strategies.

Topics: Antifungal Agents; Apoptosis; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Itraconazole; Mucorales; Tacrolimus; Triazoles

A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug), tacrolimus (an immunosuppressive agent) and floxuridine (an antimetabolite) were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.

Topics: Adenosine Triphosphate; Amphotericin B; Antifungal Agents; Ascomycota; Bithionol; Cell Line, Tumor; Drug Evaluation, Preclinical; Drug Repositioning; Floxuridine; Humans; Hyphae; Sepsis; Spores, Fungal; Tacrolimus; Triazoles

We hypothesized that tacrolimus, an inhibitor of the calcineurin pathway, would enhance the in vivo activity of posaconazole against Rhizopus oryzae, the Mucorales species most commonly associated with mucormycosis.. We examined patterns of growth inhibition and fungicidal activity of posaconazole and tacrolimus, alone and in combination, against R. oryzae in vitro, using multiple methods (ie, hyphal metabolic and fluorescent vital dye reduction assays and measurement of chitin concentrations), and in vivo, using 2 mucormycosis models: an invertebrate model (Drosophila) and a nonlethal murine model of cutaneous mucormycosis.. Combinations of posaconazole and tacrolimus were synergistic in checkerboard assays for 4 clinical isolates of R. oryzae (48-hour fractional inhibitory concentration index, 0.187-0.281). Pharmacodynamic analysis of the combination revealed that the 90% effective concentration threshold of posaconazole activity against R. oryzae could be achieved with 2-fold lower drug concentrations (0.5-1 mg/L) when administered with tacrolimus (0.007-2 mg/L). In vivo, combination therapy was associated with improved survival in the fly model of mucormycosis (65% vs 57% posaconazole alone) and with significant reductions in cutaneous lesions and R. oryzae fungal burden, compared with animals that received posaconazole monotherapy, in the cutaneous model of mucormycosis.. Combination posaconazole-tacrolimus therapy displays synergism in vitro and improved antifungal efficacy in vivo in 2 phylogenetically distinct models of mucormycosis.

Topics: Animals; Antifungal Agents; Disease Models, Animal; Drosophila; Drug Synergism; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mucormycosis; Rhizopus; Tacrolimus; Treatment Outcome; Triazoles

Zygomycosis is an uncommon but devastating disease with few therapeutic options. Calcineurin inhibitors and sirolimus (mTOR inhibitor), commonly used in transplant patients as immunosuppressives, have antifungal activity. They are known to demonstrate synergy with triazoles against certain fungi, though limited data exist about their activity against zygomycetes. Our aim was to study the in vitro interaction of posaconazole with calcineurin inhibitors and sirolimus against zygomycetes.. Drug interactions were assessed with chequerboard dilution for posaconazole with calcineurin inhibitors and sirolimus according to the CLSI M38-A2 method for filamentous fungi. Twenty-eight clinical isolates were studied, including Rhizopus arrhizus, Rhizopus microsporus, Rhizomucor pusillus, Mucor sp., Cunninghamella bertholletiae, Myocladus corymbifera and Apophysomyces elegans. Combinations of posaconazole with tacrolimus, cyclosporin A or sirolimus were used. Experiments were performed in duplicate. Mean fractional inhibitory concentration indices were calculated.. Posaconazole with calcineurin inhibitors demonstrated consistent synergy against C. bertholletiae, M. corymbifera and A. elegans, whereas synergy or no interaction was primarily observed against R. arrhizus, R. microsporus, R. pusillus and Mucor. Antagonism was seen with the combination of posaconazole and sirolimus. Strain variability was noted among the same species.. The clinical significance of these findings is unclear, but further studies are warranted given the potential for concomitant use of these agents in transplant patients treated for zygomycosis.

Topics: Antifungal Agents; Calcineurin; Cyclosporine; Drug Interactions; Humans; Mucorales; Sirolimus; Tacrolimus; Triazoles

The in vitro interaction of antifungals with immunosuppressive drugs was evaluated against zygomycetes. The combination of amphotericin B with cyclosporine, rapamycin, or tacrolimus was synergistic for 90%, 70%, and 30% of the isolates, respectively. For posaconazole, itraconazole, and ravuconazole, synergy was more frequently observed with cyclosporine than with rapamycin or tacrolimus and antagonistic interactions were rarely noted. In summary, calcineurin inhibitors and rapamycin can be synergistic in vitro with amphotericin B and azoles against zygomycetes.

Topics: Amphotericin B; Antifungal Agents; Azoles; Cyclosporine; Drug Interactions; Immunosuppressive Agents; Itraconazole; Microbial Sensitivity Tests; Mucorales; Rhizopus; Sirolimus; Tacrolimus; Thiazoles; Triazoles

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

Calcineurin inhibitors may augment the effects of antifungal drugs in microbiological assays. We examined this interaction in a microbiological assay for posaconazole. No effect was observed. However, concurrent or recently discontinued treatment with other antifungal drugs caused false-positive results, emphasizing a limitation of microbiological assays for antifungal drug level measurement.

Topics: Antifungal Agents; Calcineurin Inhibitors; Cyclosporine; Drug Interactions; False Positive Reactions; Graft vs Host Disease; Humans; Immunosuppressive Agents; Microbiological Techniques; Sirolimus; Tacrolimus; Triazoles