sirolimus and Mycoses

The high incidence and mortality of invasive fungal infections and serious drug resistance have become a global public health issue. The ability of fungal cells to form biofilms is an important reason for the emergence of severe resistance to most clinically available antifungal agents. Targeting fungal biofilm formation by small molecules represents a promising new strategy for the development of novel antifungal agents. This perspective will provide a comprehensive review of fungal biofilm inhibitors. In particular, discovery strategies, chemical structures, antibiofilm/antifungal activities, and structure-activity relationship studies will be discussed. Development of inhibitors to treat biofilm-related resistant fungal infections is a new yet clinically unexploited paradigm, and there is still a long way to go to clinical application. Better understanding of fungal biofilms in combination with systematic drug discovery efforts will pave the way for potential clinical applications.

Topics: Animals; Antifungal Agents; Biofilms; Drug Discovery; Drug Resistance, Fungal; Fungi; Humans; Models, Molecular; Mycoses; Small Molecule Libraries

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

Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is a potent immunosuppressant that is increasingly used in prevention and treatment of graft-vs-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) patients. However, data regarding its adverse effects in HSCT patients remain limited. We describe an 18-year-old HSCT patient with a history of invasive fungal infection, who developed pericardial effusion with cardiac tamponade and interstitial pneumonitis while receiving sirolimus for GVHD prophylaxis. Our case illustrates potentially life-threatening complications of sirolimus use in allogeneic HSCT patients.

Topics: Adolescent; Cardiac Tamponade; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Mycoses; Pericardial Effusion; Postoperative Complications; Recurrence; Siblings; Sirolimus

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

Azole antifungals, prescribed prophylactically to avoid severe infections in immunosuppressed organ transplant recipients, can interact with drug substrates of CYP3A4. We report serious adverse effects due to interaction between orally administered voriconazole and everolimus in a renal transplant recipient.. Despite reduction of the dose of everolimus by a third, the blood trough concentration of everolimus increased considerably in a kidney transplant recipient upon oral administration of voriconazole. Everolimus was then discontinued. Pneumonia secondary to pulmonary aspergillosis worsened, possibly due to the excessive immunosuppression.. Orally administered voriconazole inhibits intestinal and hepatic cytochrome P450-3A4 activity and thereby reduces everolimus metabolism. An 80% decrease in dose or discontinuation of everolimus is required when concomitant voriconazole is introduced. Daily blood monitoring of everolimus is warranted until a steady state of concentrations is reached.

Topics: Administration, Oral; Aged; Antifungal Agents; Drug Interactions; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycoses; Pneumonia; Sirolimus; Voriconazole

The target of rapamycin (TOR) is a critical regulator of growth, survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin has been used extensively to elucidate the TOR related signal pathway but is limited by its inability to inhibit TORC2. We used an unbiased cell proliferation assay of a kinase inhibitor library to discover QL-IX-55 as a potent inhibitor of S. cerevisiae growth. The functional target of QL-IX-55 is the ATP-binding site of TOR2 as evidenced by the discovery of resistant alleles of TOR2 through rational design and unbiased selection strategies. QL-IX-55 is capable of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2) as demonstrated by biochemical IP kinase assays (IC(50) <50 nM) and cellular assays for inhibition of substrate YPK1 phosphorylation. In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent transcription, which suggests that this compound will be a powerful probe to dissect the Tor2/TORC2-related signaling pathway in yeast.

Topics: Adenosine Triphosphate; Antifungal Agents; Cell Cycle Proteins; Humans; Models, Molecular; Mycoses; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Sirolimus; Transcription Factors

Sirolimus is used in allogeneic hematopoietic stem cell transplants (HSCTs) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this population for invasive fungal disease (IFD) prophylaxis and treatment. As posaconazole strongly inhibits CYP3A4, concurrent administration of sirolimus, a CYP3A4 substrate, and posaconazole has been reported to increase sirolimus drug exposure substantially. Coadministration of posaconazole and sirolimus is contraindicated by the manufacturer of posaconazole. We identified 15 patients who underwent HSCTs at our institution receiving a steady-state dose of sirolimus who subsequently started posaconazole therapy from January 2006 to March 2009. We recorded baseline characteristics, drug administration details, and potential adverse effects related to either drug. All patients underwent HSCTs for treatment of hematologic malignancy. All patients were initially prescribed sirolimus for GVHD prophylaxis and continued therapy after developing GVHD. Twelve patients (80%) received posaconazole for IFD prophylaxis in the setting of GVHD and 3 (20%) for IFD treatment. Patients received sirolimus and posaconazole concurrently for a median of 78 days (interquartile range [IQR] 25-177; range, 6-503). The median daily dose of sirolimus (2 mg/day) before initiation of posaconazole was reduced 50% to a median daily dose of 1 mg/day at steady state. Six patients experienced sirolimus trough levels greater than 12 ng/mL during coadministration, but only 1 patient experienced an adverse event potentially associated with sirolimus exposure during the first month of coadministration. This patient's sirolimus dose was empirically reduced by only 30% on posaconazole initiation. Concurrent sirolimus and posaconazole use seems to be well tolerated with a 33% to 50% empiric sirolimus dose reduction and close monitoring of serum sirolimus trough levels at the time of posaconazole initiation.

Topics: Adult; Antifungal Agents; Drug Administration Schedule; Drug Dosage Calculations; Drug Synergism; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycoses; Sirolimus; Transplantation, Homologous; Triazoles

Sirolimus is increasingly used in transplantation for prevention and treatment of graft-versus-host disease and organ rejection. Voriconazole is contraindicated when used concomitantly with sirolimus because of a substantial increase in sirolimus drug exposure with unadjusted dosing, but voriconazole is also considered the best initial treatment of invasive aspergillosis and other fungal infections. Patients who received voriconazole and sirolimus concomitantly were identified by a review of the medical records of all allogeneic hematopoietic stem cell recipients at our institution from September 1, 2002, to June 1, 2005. Data including baseline characteristics, indications for both drugs, and potential adverse effects were evaluated. Eleven patients received voriconazole and sirolimus concomitantly for a median of 33 days (range, 3-100 days). In 8 patients whose sirolimus dose was initially reduced by 90%, trough sirolimus levels were similar to those obtained before the administration of voriconazole; no obvious significant toxicity from either drug was observed during coadministration. Serious adverse events were observed in 2 patients in whom sirolimus dosing was not adjusted during voriconazole administration. Sirolimus and voriconazole may be safely coadministered if there is an empiric initial 90% sirolimus dose reduction combined with systematic monitoring of trough levels.

Topics: Adult; Antifungal Agents; Cord Blood Stem Cell Transplantation; Creatinine; Dose-Response Relationship, Drug; Drug Evaluation; Drug Interactions; Female; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Leukemia; Lipids; Male; Middle Aged; Mycoses; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Pyrimidines; Retrospective Studies; Sirolimus; Transplantation, Homologous; Triazoles; Voriconazole