mycophenolic-acid and Aspergillosis

In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for sepsis associated with immunosuppressive medications that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis.. The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee.. The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al. on p. S591.. Immunosuppressed patients, by definition, are susceptible to a wider spectrum of infectious agents than immunologically normal patients and, thus, require a broader spectrum antimicrobial regimen when they present with sepsis or septic shock. Special expertise managing immunosuppressed patient populations is needed to predict and establish the correct diagnosis and to choose appropriate empiric and specific agents and maximize the likelihood that patients will survive these microbial challenges.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Antibodies, Monoclonal; Antifungal Agents; Antiviral Agents; Aspergillosis; Candidiasis; Consensus Development Conferences as Topic; Evidence-Based Medicine; Hepatitis, Viral, Human; Humans; Immune Tolerance; Immunocompromised Host; Immunophilins; Immunosuppressive Agents; Mycophenolic Acid; Pneumonia; Practice Guidelines as Topic; Sepsis; Shock, Septic; Tumor Necrosis Factor-alpha

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at high risk for invasive aspergillosis. Whereas adoptive immunotherapy transferring donor-derived anti-Aspergillus TH1 cells has been shown to be beneficial for HSCT recipients suffering from invasive aspergillosis, little is known about the impact of commonly used immunosuppressants on the functional properties of anti-Aspergillus TH1 cells. Anti-Aspergillus TH1 cells were coincubated with different concentrations of methylprednisolone, cyclosporine (CsA), mycophenolic acid (MPA), the active component of mycophenolate mofetil, and rapamycin. Immunosuppressants were tested in concentrations reflecting common target levels in serum and in significantly lower and higher concentrations. Apoptosis of anti-Aspergillus TH1 cells, as well as proliferation and production of gamma interferon (IFN-γ) and CD154 upon restimulation, was evaluated in the presence and absence of immunosuppressive compounds. All dosages of CsA, MPA, and methylprednisolone significantly decreased the number of viable anti-Aspergillus TH1 cells in the cell culture, which was due partly to an impaired proliferative capacity of the cells and partly to an increased rate of apoptosis. In addition, CsA significantly decreased the number of IFN-γ-producing cells and had the highest impact of all immunosuppressants on IFN-γ levels in the supernatant. CsA also significantly decreased the expression of CD154 by anti-Aspergillus TH1 cells. Variant dosages of immunosuppressants exhibit particular effects on essential functional properties of anti-Aspergillus TH1 cells. Our findings may have an important impact on the design of clinical trials evaluating the therapeutic benefit of anti-Aspergillus TH1 cells in allogeneic HSCT recipients suffering from invasive aspergillosis.

Topics: Apoptosis; Aspergillosis; Aspergillus fumigatus; Cell Proliferation; Cells, Cultured; Cyclosporine; Cytokines; Humans; Immunosuppressive Agents; Interferon-gamma; Methylprednisolone; Mycophenolic Acid; Sirolimus; Th1 Cells

Topics: Abscess; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Biopsy, Fine-Needle; Caspofungin; Contraindications; Cyclosporine; Delayed Graft Function; Drug Interactions; Echinocandins; Fever of Unknown Origin; Gram-Negative Bacterial Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lipopeptides; Male; Middle Aged; Mycophenolic Acid; Peptides, Cyclic; Postoperative Complications; Prednisone; Pyrimidines; Radionuclide Imaging; Stenotrophomonas maltophilia; Surgical Wound Infection; Thyroiditis; Triazoles; Ultrasonography; Voriconazole

Aspergillus infection is a rare but devastating complication following organ transplantation with high mortality rate. Aspergillus fumigatus is the most common cause of invasive aspergillosis. This fungus is present in the environment worldwide. Aspergillus infection is mainly acquired by inhalation of spores and several nosocomial infections in transplant recipient have been associated with construction work at hospitals. Risk factors for invasive aspergillosis include administration of steroid boluses, history of cytomegalovirus infection, neutropenia and prolonged antibiotic use after transplantation. Successful treatment depends on three factors: early diagnosis, aggressive antifungal therapy and decrease or removal of immunosuppression. Amphotericin deoxycholate has been the standard treatment for many years but lipid preparations for amphotericin are now used due to their significantly fewer adverse effects. A number of new antifungal drugs are now being developed including new azoles such as voriconazol and echinocandin. Invasive aspergillosis has a high mortality rate more than 95% when cerebral dissemination is demonstrated. We report the case of a 47 years old woman who received a cadaveric renal graft and developed pulmonary aspergillosis with fulminant cerebral dissemination two months later. The diagnosis of pulmonary aspergillosis was by culture isolation obtained from bronchioalveolar lavage. Removal of immunosuppresive agents and liposomal amphotericin B therapy were started shortly after admission. Brain CT scan performed on the 12th day showed cerebral dissemination. The recipient died two days later. Our patient had several risk factors such as the administration of steroid boluses and cytomegalovirus infection. Invasive aspergillosis must be always included in the differential diagnosis of fever and pulmonary disease in the renal transplant recipient.

Topics: Amphotericin B; Aspergillosis; Aspergillus fumigatus; Cross Infection; Cyclosporine; Cytomegalovirus Infections; Fatal Outcome; Female; Fever; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Liposomes; Lung Diseases, Fungal; Middle Aged; Mycophenolic Acid; Neuroaspergillosis; Neutropenia; Polycystic Kidney, Autosomal Dominant; Prednisone; Risk Factors

(1) Invasive aspergillosis is rare. It usually occurs in immunocompromised patients and is fatal despite treatment in 40-90% of cases. The reference treatments are standard amphotericin B, liposomal amphotericin B, and itraconazole. (2) Caspofungin, an antifungal drug, is now approved in the Europe Union for the treatment of invasive aspergillosis, when reference drugs fail or are poorly tolerated. (3) In a non comparative trial in 69 patients, intravenous caspofungin infusion was at least partly effective: 40% of patients survived with few relapses for at least one year following treatment. A historical comparison also favours caspofungin therapy. (4) The safety profile of caspofungin is poorly documented. It includes local reactions at the injection site, systemic reactions linked to the infusion (especially due to histamine release) and hepatic disorders. (5) Caspofungin is known to interact with tacrolimus (lower tacrolimus concentrations), ciclosporin (increased caspofungin bioavailability) and rifampicin (reduced caspofungin bioavailability). (6) In practice, caspofungin is an acceptable option for the treatment of invasive aspergillosis when standard amphotericin B, liposomal amphotericin B, and itraconazole are ineffective or poorly tolerated. Its clinical assessment is limited and must be continued.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Clinical Trials as Topic; Drug Approval; Drug Interactions; France; Humans; Itraconazole; Lung Diseases, Fungal; Mycophenolic Acid; Peptides; Treatment Outcome