tacrolimus and Mycoses

With the increasing morbidity and mortality of invasive fungal infections and the emergence of severe antifungal drug resistance, new drug targets and novel antifungal agents are urgently needed. Recently, better understanding of fungal pathogenesis has contributed to the rapid emergence of potential antifungal drug targets. This perspective aims to provide a comprehensive review of new antifungal targets and of medicinal chemistry efforts toward inhibitor discovery. Particular focus will be placed on the druggability of the targets and their potential to treat resistant fungal infections. Innovative strategies for the next generation of antifungal therapy, such as virulence factors, protein-protein interactions, and immune response-based proteins, will also be highlighted.

Topics: Antifungal Agents; Drug Resistance, Fungal; Humans; Molecular Targeted Therapy; Mycoses

Chronic otitis externa (COE) remains a frustrating problem for both patient and physician. The end stage of disease, medial fibrosing otitis externa, is very challenging to repair. New and old therapies and promising approaches to the treatment of this often recalcitrant problem are presented in this review.. Tacrolimus, a nonsteroidal immunosuppressant, and fluocinolone acetonide oil 0.01%, a medium-high potency steroid preparation, may offer additional therapeutic options in the struggle against this inflammatory ear canal/skin condition of often unknown cause. Relative potencies of many steroid preparations will be presented along with several treatment strategies for controlling COE. Underlying autoimmune problems such as Sjögren's disease, sarcoidosis, and amyloidosis must be searched and, if present, addressed and treated for resolution of symptoms. Cutting edge therapies, including use of bacteriophages and inflammatory proteases, will also be reviewed.. No single therapy will be successful for every patient with COE. The search for an underlying cause, the removal of all possible irritants to the ear canal skin (e.g. Q-tips, water), debridement, and both topical and occasionally, systemic therapy will control (not cure …) the disease process in the vast majority of patients.

Topics: Anti-Inflammatory Agents; Bacterial Infections; Bacteriophages; Chronic Disease; Debridement; Fluocinolone Acetonide; Humans; Immunosuppressive Agents; Mycoses; Otitis Externa; Peptide Hydrolases; Tacrolimus

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

Invasive fungal infections are rising worldwide as the number of immunocompromised patients increases. Unfortunately, our armamentarium of antifungal drugs is limited. Although current therapies are effective in treating some of the most prevalent infections, the development of novel treatments is vital because of emerging drug-resistant strains and species and because of the toxicity of certain current therapies. The immunosuppressive drugs CsA (cyclosporin A), FK-506 (tacrolimus) and rapamycin (sirolimus) exert potent antifungal effects against a variety of pathogenic fungi. These compounds are all currently in clinical use as immunosuppressive therapy to treat and prevent rejection of transplanted organs. Rapamycin is also in clinical trials as an antiproliferative agent for chemotherapy and invasive cardiology. Recent studies reveal a potent fungicidal synergism between azoles and the calcineurin inhibitors CsA and FK-506, and animal studies demonstrate that the CsA-fluconazole synergistic combination has therapeutic benefit. Less immunosuppressive analogs have been identified with potential to enhance current therapies, or as monotherapy without deleterious effects on the immune system. In summary, these highly successful pharmaceutical agents may find an even broader clinical application in combating infectious diseases.

Topics: Animals; Antifungal Agents; Calcineurin Inhibitors; Cyclosporine; Fungi; Humans; Immunophilins; Immunosuppressive Agents; Mycoses; Sirolimus; Tacrolimus

Alternaria is a saprophytic fungus that is increasingly recognized as a human pathogen, particularly in immunocompromised hosts, including solid-organ transplant recipients. Although combined surgical and medical treatment seem to be useful in the management of this infection, an optimal antifungal therapy remains to be defined. Only four cases of alternariosis after orthotopic liver transplantation have been reported. We describe an additional case and review the literature on infections due to Alternaria in organ transplant recipients, with special emphasis on treatment.

Topics: Alternaria; Antifungal Agents; Humans; Immunosuppressive Agents; Itraconazole; Liver Transplantation; Male; Middle Aged; Mycoses; Tacrolimus

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

Itraconazole is often given for fungal prophylaxis to lung transplant recipients after transplantation. The aim of this study was to determine the extent of interaction between tacrolimus and itraconazole in lung transplant recipients and the efficacy of itraconazole prophylaxis.. The study group included 40 lung transplant recipients followed for at least 12 months. All received prophylactic itraconazole, 200 mg twice a day, for the first 6 months after transplantation. Tacrolimus levels and dosage requirements were compared during and after itraconazole therapy. Rejection rate, fungal infection rate, and renal function were assessed. The mean cost per daily treatment of the itraconazole/tacrolimus combination and tacrolimus alone was calculated.. The mean tacrolimus dose during itraconazole treatment was 3.26 +/- 2.1 mg/day compared with 5.74 +/- 2.9 mg/day after itraconazole was stopped (p < 0.0001) for a mean total daily dose elevation of tacrolimus of 76%. When the cost of itraconazole was taken into account, the average total daily cost of the combined treatment was US5.86 dollars less than the treatment with tacrolimus alone. No differences in the rejection or fungal infection rate, or in renal toxicity, were observed between the periods with and without itraconazole treatment, although less positive fungal isolates were identified during itraconazole therapy.. Prophylaxis therapy with itraconazole is highly effective. Itraconazole reduces the dose of tacrolimus and therefore lowers the cost of therapy without causing an increase in rejection rate and with renal function preservation.

Topics: Antifungal Agents; Drug Costs; Drug Interactions; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Itraconazole; Kidney; Lung Transplantation; Mycoses; Postoperative Complications; Tacrolimus

Topics: Antilymphocyte Serum; Azathioprine; Bacterial Infections; Cytomegalovirus Infections; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Muromonab-CD3; Mycoses; Postoperative Complications; Prednisolone; Prospective Studies; Sepsis; Survival Rate; Tacrolimus; Time Factors

We conducted a prospective, randomized, double-blind study comparing amphotericin B colloidal dispersion (ABCD) with amphotericin B in the empirical treatment of fever and neutropenia. Patients with neutropenia and unresolved fever after > or = 3 days of empirical antibiotic therapy were stratified by age and concomitant use of cyclosporine or tacrolimus. Patients were then randomized to receive therapy with ABCD (4 mg/[kg.d]) or amphotericin B (0.8 mg/[kg.d]) for < or = 14 days. A total of 213 patients were enrolled, of whom 196 were evaluable for efficacy. Fifty percent of ABCD-treated patients and 43.2% of amphotericin B-treated patients had a therapeutic response (P = .31). Renal dysfunction was less likely to develop and occurred later in ABCD recipients than in amphotericin B recipients (P < .001 for both parameters). Infusion-related hypoxia and chills were more common in ABCD recipients than in amphotericin B recipients (P = .013 and P = .018, respectively). ABCD appeared comparable in efficacy with amphotericin B, and renal dysfunction associated with ABCD was significantly less than that associated with amphotericin B. However, infusion-related events were more common with ABCD treatment than with amphotericin B treatment.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Colloids; Cyclosporine; Double-Blind Method; Female; Fever; Humans; Immunosuppressive Agents; Infant; Infusions, Intravenous; Kidney Function Tests; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Pilot Projects; Prospective Studies; Tacrolimus; Treatment Outcome

Topics: Bacterial Infections; Blood Pressure; Cadaver; Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Kidney Transplantation; Male; Mycoses; Patient Selection; Postoperative Complications; Prednisolone; Tacrolimus; Time Factors; Tissue Donors; Virus Diseases

Topics: Adult; Bacterial Infections; Cyclosporine; Female; Follow-Up Studies; Humans; Liver Transplantation; Male; Mycoses; Postoperative Complications; Tacrolimus; Virus Diseases

Topics: Bacterial Infections; Child; Humans; Liver Transplantation; Mycoses; Retrospective Studies; Tacrolimus; Virus Diseases

Talaromyces marneffei causes life-threatening opportunistic fungal infections in immunocompromised patients. It often has a poorer prognosis in non-human immunodeficiency virus (HIV)-infected than in HIV-infected individuals because of delayed diagnosis and improper treatment.. A 51-year-old man presented with complaints of pyrexia, cough, and expectoration that had lasted for 15 day. This patient has been taking anti-rejection medication since kidney transplant in 2011.. T marneffei pneumonia; post renal transplantation; renal insufficiency; hypertension.. Intravenous moxifloxacin was administered on admission. After the etiology was established, moxifloxacin was discontinued and replaced with voriconazole. The tacrolimus dose was adjusted based on the blood concentration of tacrolimus and voriconazole.. The patient was successfully treated and followed-up without recurrence for 1 year.. A high degree of caution should be maintained for the possibility of T marneffei infection in immunodeficient non-HIV patients who live in or have traveled to T marneffei endemic areas. Early diagnosis and appropriate treatment can prevent progression of T marneffei infection and achieve a cure. Metagenomic next-generation sequencing (mNGS) can aid the physician in reaching an early pathogenic diagnosis. Close monitoring of tacrolimus and voriconazole blood levels during treatment remains a practical approach at this time.

Topics: Antifungal Agents; HIV Infections; Humans; Kidney Transplantation; Moxifloxacin; Mycoses; Pneumonia; Tacrolimus; Talaromyces; Voriconazole

Tacrolimus, an immunosuppressant prescribed to reduce the risk of organ rejection, is metabolized by cytochrome P450 and is a substrate for P-glycoprotein. Many medications affect tacrolimus concentrations, making it difficult to maintain exposure within its narrow therapeutic index. Clotrimazole troches, prescribed to posttransplant recipients immediately for the first 30 days for oral candidiasis prevention, are considered nonsystemic. However, data suggest a potential drug interaction, affecting tacrolimus exposure. To assess the magnitude of the effect of clotrimazole on tacrolimus trough levels, 97 kidney transplant recipients, on a stable dose of tacrolimus, were retrospectively evaluated. Tacrolimus trough concentrations were analyzed 7 and 14 days before and after discontinuation of clotrimazole. The median change in tacrolimus trough level was -1.3 ng/mL (confidence interval, -2.5, -1.0; P < .001) at day 7 and -2.8 ng/mL (confidence interval, -3.3, -1.6; P < .001) at day 14 after clotrimazole discontinuation, from a median baseline of 8.9 ng/mL. Overall, a reduction in tacrolimus level was observed in 60% of patients after discontinuation of clotrimazole. When assessing the effect of race and sex, no influence was found on the degree of change in tacrolimus level after clotrimazole discontinuation. In conclusion, clotrimazole exerts a significant interaction on tacrolimus where close monitoring of tacrolimus trough levels after discontinuation of clotrimazole is warranted.

Topics: Adult; Aged; Antifungal Agents; Clotrimazole; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Mycoses; Postoperative Complications; Retrospective Studies; Tacrolimus; Young Adult

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

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited response to currently available therapies. Alveolar type II (ATII) cells act as progenitor cells in the adult lung, contributing to alveolar repair during pulmonary injury. However, in IPF, ATII cells die and are replaced by fibroblasts and myofibroblasts. In previous preclinical studies, we demonstrated that ATII-cell intratracheal transplantation was able to reduce pulmonary fibrosis. The main objective of this study was to investigate the safety and tolerability of ATII-cell intratracheal transplantation in patients with IPF.. We enrolled 16 patients with moderate and progressive IPF who underwent ATII-cell intratracheal transplantation through fiberoptic bronchoscopy. We evaluated the safety and tolerability of ATII-cell transplantation by assessing the emergent adverse side effects that appeared within 12 months. Moreover, pulmonary function, respiratory symptoms, and disease extent during 12 months of follow-up were evaluated.. No significant adverse events were associated with the ATII-cell intratracheal transplantation. After 12 months of follow-up, there was no deterioration in pulmonary function, respiratory symptoms, or disease extent.. Our results support the hypothesis that ATII-cell intratracheal transplantation is safe and well tolerated in patients with IPF. This study opens the door to designing a clinical trial to elucidate the potential beneficial effects of ATII-cell therapy in IPF.

Topics: Adrenal Cortex Hormones; Aged; Alveolar Epithelial Cells; Anti-Infective Agents; Bacterial Infections; Bronchoscopy; Cell Transplantation; Disease Progression; Female; Forced Expiratory Volume; Ganciclovir; Graft Rejection; Humans; Idiopathic Pulmonary Fibrosis; Immunosuppressive Agents; Leucovorin; Male; Middle Aged; Mycophenolic Acid; Mycoses; Nystatin; Pulmonary Diffusing Capacity; Tacrolimus; Trachea; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Valganciclovir; Virus Diseases; Vital Capacity; Walk Test

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

Concomitant administration of the triazole antifungals, voriconazole or itraconazole, with tacrolimus can result in significant drug interaction in the transplant recipient. Limited published information exists regarding tacrolimus dosing when transitioning from voriconazole to itraconazole. The objective of this study was to evaluate the extent of the drug interaction with antifungal prophylaxis using voriconazole followed by a change to itraconazole in lung transplant recipients receiving tacrolimus.. This prospective study included lung transplant recipients receiving antifungal prophylaxis with voriconazole followed by a switch to itraconazole. Patients were followed from the time of transplant until two months after converting to itraconazole. All patients received standard immunosuppression with tacrolimus, mycophenolate mofetil, and a corticosteroid. Tacrolimus dose normalized concentrations using concentration/dose ratio were compared while receiving voriconazole versus itraconazole.. Twenty lung transplant recipients were included in the final analysis. No difference was found with the tacrolimus dose normalized concentrations on voriconazole 254 ± 28 (ng/mL)/(mg/kg) compared with itraconazole 234 ± 34 (ng/mL)/(mg/kg), p = 0.65.. Tacrolimus dosage adjustments were not necessary when converting from voriconazole to itraconazole. Validation in a larger population is needed to confirm these findings.

Topics: Adult; Aged; Antibiotic Prophylaxis; Antifungal Agents; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Itraconazole; Lung Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Prognosis; Prospective Studies; Tacrolimus; Voriconazole

To investigate the factors in association with colorectal disorders in adult renal transplant recipients.. A retrospective cohort study was carried out with clinical, microbiological and management data regarding diarrhea in 513 renal transplant recipients from Jan. 2007 to Dec. 2012.. Of the 513 patients, 118(23.00%) with no history of ulcerative colitis, were found to have diarrhea after kidney transplantation. In the 118 patients, diarrhea was probably caused by administration of immunosuppressive agents in 65 cases (55.08%), in 30 cases (25.42%) diarrhea was antibiotics associated, and in 23 cases (19.49%) it was due to infections, including bacterial, fungal and viral infections. Diarrhea occurred soon after transplantation in most cases. Of the 118 patients, the symptom of diarrhea occurred in the first 1 month in 84 cases (71.19%), and in the next 5 months in 16 cases (13.56%), and the other 18 cases (15.05%) occurred after 180 days after transplantation. Of the 118 patients, 84 cases (71.19%) were relieved or cured after proper diets, the symptomatic therapy or the adjust meat of the doses of immunosuppressive agents: 18 cases (15.25%) needed to use or adjust the antibiotics , 16 cases (13.56%) had to stop mycophenolate mofetil and convert to other drugs.. Immunosuppressive agents, antibiotics and infection are the common causes of diarrhea after kidney transplantation. The outcome is good with appropriate conservative management.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Child; Cyclosporine; Cytomegalovirus Infections; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Mycoses; Retrospective Studies; Tacrolimus; Young Adult

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

Immunosuppressive regimens for lung transplantation frequently fail to prevent rejection and are toxic. Alemtuzumab was used as induction to investigate whether oral immunosuppression could be reduced. From November 2006 to March 2008, 20 consecutive lung transplant patients received alemtuzumab induction, with reduced maintenance immunosuppression; tacrolimus (target level 10 ng/ml), mycophenolate mofetil (MMF) 250 mg bid and prednisone 7.5 mg. Twenty control cases transplanted before 2006 were treated with standard immunosuppression; tacrolimus (target level 10 ng/ml), MMF 750 mg bid and prednisone 15 mg qd. End-points included patient and graft survival, acute rejection (AR) and infection rate. There were no significant differences in six-month and 12-month survival (alemtuzumab 90% vs. controls 95%, P=0.52 and 76% vs. 95%, respectively, P=0.19). AR events were similar (alemtuzumab 2/16 vs. controls 5/20, P=0.43) - as were - bacteria positive bronchoalveolar lavage (BAL) cultures (alemtuzumab 4.9+/-7.3 per patient per year vs. controls 2.7+/-3.3, P=0.26) and viral or fungal infections (alemtuzumab 0.4+/-1.4 per patient per year vs. controls 0.1+/-0.3, P=0.87; alemtuzumab 3.9+/-6.6 vs. controls 2.3+/-1.9, P=0.57, respectively). Alemtuzumab induction and reduced immunosuppression appears to offer comparable early survival, rejection and infection rates to high-dose standard immunosuppression.

Topics: Administration, Oral; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Bronchitis; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Length of Stay; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Mycoses; Prednisone; Respiratory Function Tests; Retrospective Studies; Risk Assessment; Tacrolimus; Time Factors; Treatment Outcome; Virus Diseases

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

Aprepitant (AP) is a known inhibitor of cytochrome P450 3A4 which may affect tacrolimus metabolism. We retrospectively examined the effect of oral AP on intravenous tacrolimus concentrations in 26 patients undergoing reduced intensity transplantation from 09/2005 to 09/2006. Oral AP 125 mg daily was administered on transplant day +1 and 80 mg on days +2 and +3. Intravenous tacrolimus was administered as a 0.03 mg/kg/day continuous infusion on day -6 through day +1 (pre-AP), during-AP (days +2 to +7), and post-AP starting on day +8. Tacrolimus doses were adjusted to achieve concentrations of 5-20 ng/mL. Dose-corrected tacrolimus concentrations (ng/mL/mg per dose) in the pre-AP, during-AP, and post-AP time periods were: 8.12 (95% CI: 7.3-9.1), 11.63 (95% CI: 9.63-13.63), and 11.42 (95% CI: 8.12-14.7), respectively (P<0.01 between pre-AP and during-AP, P<0.01 between during-AP and post-AP, P = 0.01 between pre-AP and post-AP time periods). Although statistically significant, the observed rise was not clinically significant between during-AP and post-AP time periods. Previous work has shown that AP is not expected to exert an inhibitory effect within 48 h of AP discontinuation. Collectively, these data suggest that AP effect on tacrolimus metabolism is of minor clinical significance. A controlled trial is needed to confirm these findings.

Topics: Adolescent; Adult; Antiemetics; Antifungal Agents; Aprepitant; Dose-Response Relationship, Drug; Drug Interactions; Female; Fluconazole; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Injections, Intravenous; Liver Function Tests; Male; Middle Aged; Morpholines; Mycoses; Retrospective Studies; Tacrolimus; Young Adult

Topics: Antifungal Agents; Aspergillus; Benzoquinones; Biological Evolution; Calcineurin; Calcineurin Inhibitors; Candida albicans; Cyclosporine; Drug Resistance, Fungal; Drug Therapy, Combination; Ergosterol; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mutation; Mycoses; Phenotype; Quinones; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Tacrolimus

Azole antifungals inhibit the metabolism of tacrolimus mediated by CYP3A4. Upon initiation of azole therapy, the required dose reduction of tacrolimus is unknown. We reviewed our experience with azole antifungals in our pediatric thoracic transplant population receiving tacrolimus. Tacrolimus levels and dosage requirements were compared before and during azole therapy. Thirty-one patients received both tacrolimus and an azole antifungal (fluconazole = 9, itraconazole = 22). The tacrolimus dose was empirically reduced by approximately one-third when azole therapy was initiated. Mean tacrolimus dose requirements decreased by 68% within the first month of therapy (pre-azole: 0.27 +/- 0.14 mg/kg/day; 30 day post-azole: 0.087 +/- 0.069 mg/kg/day; p < 0.001). Despite a mean decrease in tacrolimus dose from baseline of 33, 42, and 55% on day 1, 2, and 4 of azole therapy, respectively, there was still an unintended 38% increase in tacrolimus levels during the first month of azole therapy. A calculated dose-reduction protocol of 50% on day of azole initiation, 70% on day 3, and 75% on day 14 should result in minimal mean changes in the tacrolimus levels. There was no difference in tacrolimus dose reduction between fluconazole and itraconazole groups. Azole antifungals markedly decrease tacrolimus requirements within the first few days of therapy. An initial reduction in tacrolimus dose by one-third is insufficient, and dose reduction of at least 50% upon azole initiation seems warranted. Once azole antifungal therapy is initiated, frequent therapeutic drug monitoring is required.

Topics: Analysis of Variance; Antifungal Agents; Child; Female; Fluconazole; Humans; Immunosuppressive Agents; Itraconazole; Male; Mycoses; Organ Transplantation; Retrospective Studies; Tacrolimus

As experience with tacrolimus (FK506, Prograf) accumulates and reduced rejection rates are increasingly demonstrated, some transplant centers are adopting tacrolimus-based primary immunosuppressive regimens for their patients undergoing pancreas/kidney transplantation. The guidelines provided in this article based on the experience of four major US transplant centers, cover issues related to dosing, blood levels, concomitant use of mycophenolate mofetil (MMF), antifungal and antiviral prophylaxis, and drug interactions. For post-transplant immunosuppression some centers initiate oral tacrolimus administration on postoperative day 1, 2, or 3, while others wait until day 6 or 7, when renal or gastrointestinal function has resumed. Most centers endeavor to achieve higher target trough levels (approximately 10-20 ng/mL, but not higher) in the first 3 months post-transplant, reducing levels thereafter. Several centers are now using MMF instead of azathioprine as an adjunct to tacrolimus. Conversion from cyclosporine to tacrolimus during maintenance therapy is often considered in the event of rejection or when adverse events do not respond to dosage reduction.

Topics: Administration, Oral; Antifungal Agents; Antiviral Agents; Drug Interactions; Drug Therapy, Combination; Fluconazole; Graft Rejection; Guidelines as Topic; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Mycoses; Pancreas Transplantation; Tacrolimus; United States; Virus Diseases

Invasive fungal infections and their risk factors were prospectively assessed in 130 consecutive liver transplant recipients receiving tacrolimus as the primary immunosuppressive agent. Eleven percent (14) of the 130 patients had 17 episodes of invasive fungal infections. These included candidiasis (5%; 6 patients), cryptococcosis (5%; 6), aspergillosis (3%; 4), and chromomycosis (1%; 1). An elevated pretransplantation creatinine level, requirement of dialysis (pretransplantation or posttransplantation), duration of intensive care unit stay after transplantation surgery, and antibiotic use (other than for prophylaxis) within 4 weeks of transplantation were significant risk factors for fungal infections occurring within 100 days of transplantation. For fungal infections occurring after 100 days, persistence of renal dysfunction (serum creatinine level of >2.5 mg/dL at 3 months), dialysis, and histopathologically documented recurrence of hepatitis C virus hepatitis were significant risk factors. Mortality was significantly higher among patients with fungal infections than among all other patients (57% vs. 15%; P = .0009). Our study identified specific risk factors for invasive fungal infections in liver transplant recipients receiving tacrolimus; strategies to prevent fungal infections or to initiate early antifungal therapy might be most effectively targeted at these patients.

Topics: Adult; Aged; Amphotericin B; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycoses; Prospective Studies; Tacrolimus

Topics: Antifungal Agents; Costs and Cost Analysis; Cyclosporine; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Itraconazole; Lung Transplantation; Male; Mycoses; Tacrolimus; Transplantation, Homologous

Under FK506-based immunosuppression, 16 cadaveric small bowel transplantations were performed in 15 recipients with (n = 5) or without (n = 11) the large bowel. Twelve (80%) patients are alive after 1.5 to 19 months, 11 bearing their grafts, of which 4 include colon. The actuarial one-year patient and graft survivals are 87.5% and 65.9%, respectively. Five grafts were lost to acute (n = 4) or chronic (n = 1) rejection, and 3 of these patients subsequently died after 376, 440, and 776 days total survival. Six recipients developed severe CMV infection that was strongly associated with seronegative status preoperatively and receipt of grafts from CMV positive donors; 3 died, and the other 3 required prolonged hospitalization. Currently, 9 patients are free from TPN 1-18 months postoperatively, 2 require partial TPN, and one has returned to TPN after graft removal. The results show the feasibility of small bowel transplantation but emphasize the difficulty of managing these recipients not only early but long after their operation.

Topics: Adult; Bacterial Infections; Child; Child, Preschool; Colon; Female; Graft Rejection; Humans; Infant; Intestine, Small; Male; Middle Aged; Mycoses; Organ Transplantation; Postoperative Care; Tacrolimus; Virus Diseases

Topics: Drug Interactions; Fluconazole; Humans; Immunocompromised Host; Mycoses; Organ Transplantation; Tacrolimus

Topics: Adult; Bacterial Infections; Female; Follow-Up Studies; Graft Rejection; Humans; Intestine, Small; Male; Middle Aged; Mycoses; Postoperative Complications; Prednisone; Prospective Studies; Retrospective Studies; Tacrolimus; Time Factors; Virus Diseases

This prospective study characterizes the incidence, etiology, timing, risk factors, and outcome of the infectious complications after 88 consecutive liver transplantations in 79 patients receiving tacrolimus (FK506) as primary immunosuppression with a median follow-up of 880 days. Infections occurred in 59% (47/79) of the patients, and 39% had major infections. Of the major infections, 55% were bacterial, 22% were viral, and 22% were fungal. Bacteremia accounted for 30% of major bacterial infections. Sixty percent of bacteremias occurring within the first 3 months were catheter related, while 75% of those occurring more than 3 months after transplant were of a biliary source. Patients with recurrent hepatitis C virus hepatitis and patients requiring dialysis after transplant had a significantly higher rate of infections as compared with other patients. Overall mortality was 18%, and 29% of all deaths were associated with infection. Only invasive aspergillosis was associated with infectious mortality. Our data suggest that the potent immunosuppressive agent FK506 is not associated with a higher incidence of infectious complications as compared with previous studies using CsA.

Topics: Adult; Aged; Bacterial Infections; Female; Graft Survival; Humans; Immunosuppression Therapy; Incidence; Infections; Liver Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Prospective Studies; Risk Factors; Survival Rate; Tacrolimus; Treatment Outcome; Virus Diseases

Topics: Adult; Anti-Bacterial Agents; Bacterial Infections; Humans; Immunosuppressive Agents; Liver Transplantation; Mycoses; Opportunistic Infections; Risk Factors; Tacrolimus; Virus Diseases