Formas clínicas y tratamiento de las infecciones causadas por otros hongos filamentosos

An increase in infections by filamentous fungi other than Aspergillus has been observed in the last few years. Clear fungi or hyalohyphomycetes, dematiaceous or dark fungi, agents of mucormycosis, and Pneumocystis jirovecii are generally emerging opportunistic fungi that produce disseminated infection in patients with severe immunosuppression. The clinical manifestations in this group of patients are often non-specific as their expression is modified by the disease itself or by the concomitant treatments, which difficult early diagnosis. This, together with the relatively limited therapeutic resources available, has led to invasive fungal infections by these filamentous fungi being associated with significant mortality (30-100%). Nowadays with the emergence of the new triazole drugs or lipid formulations of amphotericin B, often combined with other antifungal drugs, attempts are being made to change the dire prognosis of patients with these infections.     

Drug‐drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4

Patients undergoing treatment with immunosuppressant drugs following solid organ or hematopoietic stem cell transplantation are at particular risk for development of serious infections such as invasive aspergillosis. Four triazole antifungal drugs, voriconazole, posaconazole, itraconazole, and isavuconazole, are approved to treat invasive aspergillosis either as first‐ or second‐line therapy. All of these agents are inhibitors of cytochrome P450 3A4, which plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, and sirolimus. Thus, co‐administration of a triazole antifungal drug with these immunosuppressant drugs can potentially increase plasma concentrations of the immunosuppressant drugs, thereby resulting in toxicity, or upon discontinuation, inadvertently decrease the respective concentrations with increased risk of rejection or graft‐versus‐host disease. In this article, we review the evidence for the extent of inhibition of cytochrome P450 3A4 by each of these triazole antifungal drugs and assess their effects on cyclosporine, tacrolimus, and sirolimus. We also consider other factors affecting interactions of these two classes of drugs. Finally, we examine recommendations and strategies to evaluate and address those potential drug‐drug interactions in these patients.     

Scedosporium prolificans pericarditis and mycotic aortic aneurysm in a lung transplant recipient receiving voriconazole prophylaxis

Despite the adoption of antifungal prophylaxis, fungal infections remain a significant concern in lung transplant recipients. Indeed, some concern exists that such prophylaxis may increase the risk of infection with drug‐resistant fungal organisms. Here, we describe a case of disseminated Scedosporium prolificans infection, presenting as pericarditis, which developed in a lung transplant patient receiving prophylactic voriconazole for 8 months. The epidemiology and clinical presentation of S. prolificans infections are reviewed, and controversies surrounding antifungal prophylaxis and the development of resistant infections are discussed.     

New approaches to invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients

Recognition and treatment of invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients are important clinical challenges. New diagnostic tools, such as fungal serologic assays and high-resolution CT scans, offer the hope for earlier initiation of antifungal therapy and improved treatment results. New antifungal agents offer choices that in some cases are less toxic than older drugs and in other cases are more efficacious. Combining the new diagnostic tools with new drugs, novel strategies are being evaluated to change our approaches to these deadly infections.     

Immunosuppressive therapy and infection after kidney transplantation

J. Fortun, P. Martin‐Davila, J. Pascual, C. Cervera, A. Moreno, J. Gavalda, J.M. Aguado, P. Pereira, M. Gurguí, J. Carratala, M. Fogueda, M. Montejo, F. Blasco, G. Bou, J. Torre‐Cisneros; RESITRA Transplant Network. Immunosuppressive therapy and infection after kidney transplantation.
Transpl Infect Dis 2010: 12: 397–405. All rights reserved Abstract: Background. The role of immunosuppressive drugs in the development of infection in transplant recipients has been poorly analyzed. Objective. To evaluate the possible association between infection and immunosuppression regimens in a large cohort of renal transplant recipients. Methods. All renal transplant recipients included in the RESITRA prospective cohort from August 2003 to February 2005 with a minimum follow‐up of 3 months were studied. An intention‐to‐treat analysis was performed and patients were analyzed in groups according to the type of induction and initial maintenance therapy. Viral, bacterial, and fungal infections occurring during this period were evaluated. Results. A total of 1398 renal transplant recipients were studied. A maintenance regimen containing sirolimus was independently associated with a lower risk of cytomegalovirus (CMV) infection (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.05–0.54) and with a higher rate of surgical site infection (OR, 3.21; 95% CI, 1.26–8.21). Excluding treatment used for acute rejection episodes, no other factors related to the immunosuppression regimens were associated with the development of bacteremia, urinary infections, pneumonia, or other infections. Conclusion. The use of sirolimus as maintenance therapy in kidney recipients is associated with a low rate of CMV infection and with a higher risk of surgical site infection.     

Antifungal drug resistance: does it matter?

The objectives of this review are: to review the modes of action of currently available antifungal drugs; to define drug resistance and discuss the mechanisms by which fungi can develop resistance to antifungal drugs; to consider the epidemiological and host factors that contribute to the outcome of antifungal therapy and whether the available in vitro susceptibility test methods can reliably predict clinical response; and to assess the overall relevance of drug resistance to the outcome of fungal infections. The incidence of antifungal drug resistance among pathogens causing invasive fungal infections appears to be increasing. In the case of Candida spp., this may in part be a consequence of selective pressure brought about by more intensive antifungal use leading to a ‘pathogen shift’. Non-albicans Candida spp. are more likely to demonstrate reduced susceptibility to fluconazole compared to C. albicans. Susceptibility breakpoints developed by the National Committee for Clinical Laboratory Standards to test azoles and flucytosine against Candida spp. are helpful in guiding therapy. Antifungal drug resistance in yeasts is of clinical importance. Increasingly reliable methods of in vitro susceptibility testing can help predict clinical response to therapy, but other considerations, including host- and drug-related factors, can also have an important bearing on the ultimate outcome of treatment.     

Necrotizing Microascus tracheobronchitis in a bilateral lung transplant recipient

Invasive fungal infections are a major cause of mortality among solid organ transplant recipients. Scopulariopsis species and their teleomorph Microascus are molds found in soil and decaying organic matter. We report here the case of a woman who underwent bilateral lung transplantation for severe emphysema. On day 25 after transplantation, endobronchial green‐black lesions were detected during routine endoscopy. Endobronchial swabs, biopsies, and bronchoalveolar lavage samples were positive for Microascus cirrosus. This fungal infection developed despite voriconazole given for previous persistent invasive aspergillosis. Treatment consisted of a combination of antifungal medication (voriconazole, terbinafine, amphotericin B, and caspofungin) and endoscopic resection of necrosed bronchial mucosa. A favorable clinical outcome was achieved after 7 weeks of treatment. Seven cases of Scopulariopsis/Microascus infection have been previously described in solid organ transplant recipients. Only two survived after treatment with an antifungal combination therapy including echinocandins, posaconazole, and terbinafine. In immunocompromised patients, infection by Microascus species is a rare but life‐threatening event because of innate resistance to most common antifungal drugs. Our patient was successfully cured by combined therapy including intravenous voriconazole and caspofungin, oral terbinafine, and inhaled voriconazole and amphotericin B administered for 7 weeks in association with iterative endoscopic debridement to reduce fungal inoculum.     

Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients

Filamentous fungal infections are associated with high morbidity and mortality in solid organ transplant patients, and prevention is warranted whenever possible. An increase in invasive aspergillosis was detected among solid organ transplant recipients in our institution during 1991–92. Rates of Aspergillus infection (18.2%) and infection or colonization (42%) were particularly high among lung transplant recipients. Epidemiologic investigation revealed cases to be both nosocomial and community‐acquired, and preventative efforts were directed at both sources. Environmental controls were implemented in the hospital, and itraconazole prophylaxis was given in the early period after lung transplantation. The rate of Aspergillus infection in solid organ transplant recipients decreased from 9.4% to 1.5%, and mortality associated with this disease decreased from 8.2% to 1.8%. The rate of Aspergillus infection or colonization among lung transplant recipients decreased from 42% to 22.5%; nosocomial Aspergillus infection decreased from 9% to 3.2%. Cases of aspergillosis in lung transplant recipients were more likely to be early infections in the pre‐intervention period. Early mortality in lung transplant recipients decreased from 15% to 3.2%. Two cases of dematiaceous fungal infection were detected, and no further cases occurred after environmental controls. The use of environmental measures that resulted in a decrease in airborne fungal spores, as well as antifungal prophylaxis, was associated with a decrease in aspergillosis and associated mortality in these patients. Ongoing surveillance and continuing intervention is needed for prevention of infection in high‐risk solid organ transplant patients.     

Fusarium dimerum infection in a stem cell transplant recipient treated successfully with voriconazole

We report the first case, to our knowledge, of a proven Fusarium dimerum soft-tissue infection in a stem cell transplant recipient treated successfully with voriconazole. There is a well-documented increase in the incidence, diversity and antifungal resistance of invasive mould infections in the immunocompromised patient population. The management of these infections is changing as new, more efficacious and less toxic antifungal agents become available. We present the case of a 19-year-old female diagnosed with a proven F. dimerum soft-tissue infection of the foot and possible pulmonary infection with the same organism 10 days following a sibling allogeneic stem cell transplant for severe aplastic anaemia. The infection developed despite treatment with 3 mg/kg AmBisome for a concurrent chest infection. She was treated successfully with voriconazole.     

Antifungal Drug Resistance: Mechanisms,Epidemiology, and Consequences for Treatment

Antifungal resistance continues to grow and evolve and complicate patient management, despite the introduction of new antifungal agents. In vitro susceptibility testing is often used to select agents with likely activity for a given infection, but perhaps its most important use is in identifying agents that will not work, i.e., to detect resistance. Standardized methods for reliable in vitro antifungal susceptibility testing are now available from the Clinical and Laboratory Standards Institute (CLSI) in the United States and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in Europe. Data gathered by these standardized tests are useful (in conjunction with other forms of data) for calculating clinical breakpoints and epidemiologic cutoff values (ECVs). Clinical breakpoints should be selected to optimize detection of non–wild-type (WT) strains of pathogens, and they should be species-specific and not divide WT distributions of important target species. ECVs are the most sensitive means of identifying strains with acquired resistance mechanisms. Various mechanisms can lead to acquired resistance of Candida species to azole drugs, the most common being induction of the efflux pumps encoded by the MDR or CDR genes, and acquisition of point mutations in the gene encoding for the target enzyme (ERG11). Acquired resistance of Candida species to echinocandins is typically mediated via acquisition of point mutations in the FKS genes encoding the major subunit of its target enzyme. Antifungal resistance is associated with elevated minimum inhibitory concentrations, poorer clinical outcomes, and breakthrough infections during antifungal treatment and prophylaxis. Candidemia due to Candida glabrata is becoming increasingly common, and C glabrata isolates are increasingly resistant to both azole and echinocandin antifungal agents. This situation requires continuing attention. Rates of azole-resistant Aspergillus fumigatus are currently low, but there are reports of emerging resistance, including multi-azole resistant isolates in parts of Europe.     

Daptomicina en las infecciones por bacterias grampositivas en pacientes oncohematológicos y en receptores de trasplante

Gram-positive infections are a major cause of morbidity and mortality in oncohematological patients and transplant recipients. The most frequently isolated Gram-positive organisms are the coagulase-negative staphylococci, Staphylococcus aureus and Enterococcus spp., and viridans group streptococci. Antibiotic resistance in these organisms is increasing and poses a challenge to clinicians. Daptomycin is rapidly bactericidal against a broad spectrum of gram-positive bacteria, including strains resistant to other drugs. The present article reviews some aspects of Gram-positive infections in these immunocompromised patients and provides a detailed analysis of experience with daptomycin in the treatment of these infections.     

Epidemiology and prevention of invasive aspergillosis

Aspergillus species are the most common causes of invasive mold infections in immunocompromised persons. This review examines the available information regarding the rising incidence of invasive aspergillosis in different high-risk groups, including persons with acute leukemia, hematopoietic stem cell transplant recipients, and liver and lung transplant recipients. The risk factors for infection in these groups are discussed. Because Aspergillus species are widespread in the environment, it is difficult to link specific sources and exposures to the development of human infections. However, molecular strain typing and other studies indicate that a significant number of Aspergillus infections are now being acquired outside the health care setting, either before patients are admitted to hospital, or after they have been discharged. The role of environmental control measures and antifungal drug prophylaxis in the prevention of hospital- and community-acquired aspergillosis is discussed.     

Approaches to fungal diagnosis in transplantation

The diagnosis of invasive fungal infection in patients undergoing solid organ or bone marrow transplantation remains a significant clinical challenge. Consideration of the epidemiology of these infections and host risk factors may be an important clue to a specific fungal diagnosis. Despite extensive investigation on methods such as serologic techniques to improve the rapid diagnosis of these infections, the diagnosis of invasive mycoses remains largely dependent on clinical presentation. For example, the signs and symptoms that result from angioinvasion of fungal organisms include pleuritic chest pain or hemoptysis. In a high-risk patient these findings can be important clues to invasive fungal infection. Cultures of opportunistic fungi in certain settings, such as Aspergillus in respiratory samples from immunosuppressed patients, may be associated with infection. Radiographic findings can also be useful to establish a diagnosis of infection. In patients with invasive aspergillosis as well as other angioinvasive moulds, chest CT scans may demonstrate lesions that are not visible on plain radiographs. Serodiagnosis of these infections remains largely investigational. Microbiological antifungal resistance has increasingly been reported, but in patients at high risk for serious fungal infection, including patients undergoing bone marrow and organ transplantation, antifungal resistance remains uncommon, particularly in Candida albicans. Higher doses of azoles should be used to treat patients with infections due to less susceptible yeasts and those with more serious infection. Prompt recognition of fungal infection combined with intensive antifungal therapy is needed for successful therapy.     

Minimizing the risk of recurrent or progressive invasive mold infections during stem cell transplantation or further intensive chemotherapy.

The risk of recurrence or progression of prior invasive fungal infection, predominantly due to molds, is 11-33% during subsequent stem cell transplantations or myelosuppressive chemotherapy, with a high mortality. Risk factors at the time of transplant include active infection and having received <6 weeks of antifungal therapy, while after transplant prolonged neutropenia and graft-versus-host disease requiring aggressive immunosuppression are important. The use of peripheral blood stem cells has been associated with a lower risk. Minimal data are available regarding the role of preventative strategies such as surgical resection of pulmonary lesions and prophylactic granulocyte transfusions during neutropenia, the optimal duration of antifungal prophylaxis, and the appropriate monitoring strategy. This article critically evaluates these issues and provides recommendations for the secondary prophylaxis of invasive mold infections.     

Fungal infections in patients undergoing blood and marrow transplantation

Fungal infections are currently a leading cause of infectious morbidity and mortality in patients undergoing allogeneic blood and marrow transplantation (BMT). Although the introduction of azole antifungals for prophylaxis has had a significant impact on the incidence of candidal infections (especially those caused by C. albicans and C. tropicalis), invasive aspergillosis has increased in incidence in many centers worldwide. Given the long risk period corresponding with graft-versus-host disease, and the toxicities of currently available mold-active antifungals, the development of a prevention strategy for these angioinvasive molds remains a challenge. The introduction of new antifungal drugs and adjunctive therapy to improve immune function may be beneficial in decreasing mortality associated with these infections in the future. Most importantly, a greater understanding of the pathogenesis of fungal disease and specific host risks is necessary to impact this increasingly important infection in immunocompromised hosts.     

Legionellosis in Transplantation

Legionella species are emerging opportunistic pathogens in hematopoietic stem cell and solid organ transplant recipients, associated with significant morbidity and mortality. The clinical and radiological features of Legionella infections can mimic other opportunistic pathogens in these profoundly immunocompromised patients. Diagnosis in transplant patients is challenging as non-pneumophila Legionella infections, for which these patients are at risk, cannot be identified using the urinary antigen test. Changes in management of transplant recipients and changes in Legionella epidemiology suggest that the number of transplant patients potentially exposed to Legionella spp. may be on the rise. Yet, evidence-based, transplant-specific guidelines for managing and preventing Legionella infections are not currently available. In this article, we review the epidemiology, clinical features, diagnostic challenges, treatment options, and preventive strategies of Legionella infections in these high-risk patient populations.     

Management of candidemia and invasive candidiasis

Candida species is the fourth most common cause of bloodstream infection and is the leading cause of invasive fungal infection among hospitalized patients. Acute disseminated candidiasis remains a life-threatening disease that now occurs mainly in intensive care units hospitalized patients. Delay in treatment of Candida bloodstream infections could be minimized by the development of more rapid and sensitive diagnostic techniques for the identification of Candida bloodstream infections. Current guidelines for the management of invasive candidiasis recommend fluconazole or an echinocandin as the primary therapeutic option. The optimal choice of the antifungal agent should depend on local epidemiology, prior antifungal therapy and patient's characteristics.     

Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group.

INTRODUCTION: Fungal infections occur frequently in lung transplant patients, with the highest risk being in the early postoperative period (the initial hospitalization after lung transplantation). Aspergillus is responsible for more than half of all fungal infections, and Aspergillus has even been considered a contraindication for lung transplantation because of its difficult therapy and frequently fatal outcome. The aim of this article is to evaluate the success of an antifungal prophylaxis protocol to prevent fungal infection in the immediate postoperative period in lung transplant recipients. MATERIAL AND METHODS: From March 1994 to March 1997, we performed 52 lung transplants in 31 men and 21 women who received antifungal prophylaxis with fluconazole, 400 mg/d, and aerosolized amphotericin B, 0.6 mg/kg/d, during the postoperative period. RESULTS: The mean (+/- SD) postoperative period duration was 49 +/- 27.5 days. No fungal infections were observed during this period, and all patients provided negative cultures. We also found no toxicity related to antifungal drugs. The dose of cyclosporine was easily adjusted in every recipient according to blood levels so that effective immunosuppression was not compromised. DISCUSSION: In our study, the removal of the lungs and antifungal prophylaxis with fluconazole and aerosolized amphotericin B prevented fungal infection in the postoperative period in all 52 lung transplant recipients.     

Esophageal tuberculosis with coexisting opportunistic infections in a renal allograft transplant recipient

We report a renal allograft transplant recipient with esophageal tuberculosis (TB) coinfected with herpes simplex virus (HSV) and Candida. The patient presented with oropharyngeal candidiasis and was started on fluconazole. Upper gastrointestinal endoscopy showed whitish patches with mucosal ulcers in the esophagus. Histopathological examination confirmed TB and HSV infection. The patient recovered after antiviral, antifungal, and anti‐tubercular therapy with reduction in immunosuppression. In a TB‐endemic zone, TB can coexist with opportunistic infections in an immunocompromised host.