Fungal infection-related mortality versus total mortality as an outcome in trials of antifungal agents

BACKGROUND: Disease specific mortality is often used as outcome rather than total mortality in clinical trials. This approach assumes that the classification of cause of death is unbiased. We explored whether use of fungal infection-related mortality as outcome rather than total mortality leads to bias in trials of antifungal agents in cancer patients. METHODS: As an estimate of bias we used relative risk of death in those patients the authors considered had not died from fungal infection. Our sample consisted of 69 trials included in four systematic reviews of prophylactic or empirical antifungal treatment in patients with cancer and neutropenia we have published previously. RESULTS: Thirty trials met the inclusion criteria. The trials comprised 6130 patients and 869 deaths, 220 (25%) of which were ascribed to fungal infection. The relative risk of death was 0.85 (95% CI 0.75–0.96) for total mortality, 0.57 (95% CI 0.44–0.74) for fungal mortality, and 0.95 (95% CI 0.82–1.09) for mortality among those who did not die from fungal infection. CONCLUSION: We could not support the hypothesis that use of disease specific mortality introduces bias in antifungal trials on cancer patients as our estimate of the relative risk for mortality in those who survived the fungal infection was not increased. We conclude that it seems to be reliable to use fungal mortality as the primary outcome in trials of antifungal agents. Data on total mortality should be reported as well, however, to guard against the possible introduction of harmful treatments

Antifungal agents for preventing fungal infections in solid organ transplant recipients

Background: Invasive fungal infections (IFIs) are important causes of morbidity and mortality in solid organ transplant recipients. Objectives: This study aims to systematically identify and summarise the effects of antifungal prophylaxis in solid organ transplant recipients. Search strategy: The Cochrane Central Register of Controlled Trials (Issue 3, 2003), MEDLINE (1966-June 2003), and EMBASE (1980-June 2003) were searched. Reference lists, abstracts of conference proceedings and scientific meetings (1998-2003) were handsearched. Authors of included studies and pharmaceutical manufacturers were contacted. Selection criteria: Randomised controlled trials (RCTs) in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen. Data collection and analysis: Two reviewers independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. Differences were resolved by discussion. Data were synthesised using the random effects model and expressed as relative risk (RR) with 95% confidence intervals (95% CI). Main results: Fourteen unique trials with 1497 randomised participants were included. Antifungal prophylaxis did not reduce mortality (RR 0.90, 95% CI 0.57 to 1.44). In liver transplant recipients, a significant reduction in IFIs was demonstrated for fluconazole (RR 0.28, 95% CI 0.13 to 0.57). Although less data were available for itraconazole and liposomal amphotericin B, indirect comparisons and one direct comparative trial suggested similar efficacy. Fluconazole prophylaxis did not significantly increase invasive infections or colonisation with fluconazole-resistant fungi. In renal and cardiac transplant recipients, neither ketoconazole nor clotrimazole significantly reduced invasive infections. Overall, the strength and precision of comparisons however were limited by a paucity of data. Reviewers' conclusions: For liver transplant recipients, antifungal prophylaxis with fluconazole significantly reduces the incidence of IFIs with no definite mortality benefit. Given a 10% incidence of IFI, 14 liver transplant recipients would require fluconazole prophylaxis to prevent one infection. In transplant centres where the incidence of IFIs is high, or in situations where the individual risk is great, antifungal prophylaxis should be considered

Primary Antifungal Prophylaxis in Adult Hematopoietic Stem Cell Transplant Recipients: Current Therapeutic Concepts

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90237/1/phco.29.11.1306.pd

A Study of systemic fungal infections in Renal Transplant Recipients.

BACKGROUND : Two major factors for successful organ transplantation are better control of rejection and better prevention and treatment of infections. In renal allograft recipients, immunosuppressive drug therapy is the major cause of immunocompromised status and occurrence of infections, which arise most commonly as a result of invasion by endogenous opportunists. It may also follow colonization by exogenous environmental organisms and via transfer of cytomegalovirus along with the transplanted kidney. The overall incidence of opportunistic infections varies from center to center; up to 15% of renal transplant recipients die of these infections. Clinical signs and symptoms of infection in immunocompromised patients may be concealed or imitated by the underlying disease, and a high index of clinical suspicion is vital. The unusual pathogens encountered in these patients demand thorough investigation. The success of management of opportunistic infections depends on strong clinical suspicion, early diagnosis, and prompt treatment. The challenges of early diagnosis of opportunistic infections and prompt treatment are great; the rewards are even greater. Fungi are one of the important causes of opportunistic infection in renal transplant recipients. Invasive fungal infections are among the most important causes of mortality among transplant patients. The incidence of these infections is increasing due to greater number of transplant surgeries and usage of potent immunosuppression. Although fungal infections are less common among kidney transplant recipients (1- 14%), they are responsible for significant mortality in this group of patients. The occurrence of invasive fungal infections is highest in the early post transplant period, when immunosuppression is greatest. Prolonged antifungal therapy and surgical intervention are needed for control of fungal infections. Early and prompt diagnosis of the condition and intervention is required to prevent morbidity and mortality. AIM : To study the clinical profile, risk factors for acquiring fungal infections, its outcome and the factors influencing outcome in living and deceased donor renal transplant recipients. MATERIALS & METHODS Renal transplant recipients both cadaveric and living-related during the time period between august 2008 and May 2011 admitted with systemic fungal infections in nephrology ward were included in the study. Detailed history, duration of post transplant status, nature of immunosuppression, duration and type of symptoms, and history of other co morbid illnesses predisposing to fungal infections like Diabetes Mellitus and viral infections like HIV, HCV and CMV were taken. Data gathered included age, sex, date of transplantation, date of diagnosis, fungal pathogen, organs affected by infection, treatment and patient outcome. General examination and systemic examination followed by detailed examination of systems involved like eye, ENT, respiratory tract, GI tract etc. were done. Routine investigations like urinalysis & culture, complete hemogram, blood sugar, renal function tests, liver function tests, blood culture (bacterial & fungal), imaging of brain, Para nasal sinuses, thorax and abdomen ( like x-ray, USG, CT scan) were done. CONCLUSIONS : 1. Candida species was the commonest fungal pathogen causing infection in the renal transplant recipients (62%). 2. Gastrointestinal, lung and urinary tracts were the common sites of fungal infection (22% each). 3. Majority of fungal infections occurred in the first year (64%). 4. Graft dysfunction predisposed to the occurrence of fungal infections. 5. The mortality rate was 50%. 6. Leucopenia (82%) and thrombocytopenia (66%) were associated with high mortality

ESCMID-ECMM guideline : diagnosis and management of invasive aspergillosis in neonates and children

ACKNOWLEDGEMENT Prof Warris is supported by the Wellcome Trust Strategic Award (grant 097377) and the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of Aberdeen. FUNDING European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM)Peer reviewedPostprintPostprin

Study of the humoral and cellular immune response : to Saccharomyces cerevisiae in man

Saccharomyces cerevisiae (bakers'/brewers' yeast) is a ubiquitous dietary constituent in the developed world. Previous studies, using semi-quantitative ELISA techniques, suggested that patients with Crohn's disease have higher titres of IgG and IgA isotypespecific antibodies to this yeast than are found in normal control subjects or patients with ulcerative colitis. For this study, in order to allow more stringent assay standardisation and more meaningful numerical comparison of the relative antigen-binding capacities of different sera, a quantitative ELISA was developed for measurement of anti-yeast antibodies, using a soluble extract of yeast (sacc) as the antigen. The finding of raised levels of yeast antibodies in Crohn's disease was confirmed, and the data suggest that this may be related to the presence of disease in the small bowel, although this latter observation did not reach statistical significance. Patients with chronic liver disease also had higher antibody levels than controls, but less markedly so than in Crohn's disease. When sera were tested in a similar assay for antibodies to bovine casein, no difference was found between controls and the Crohn's or liver disease group. The response of peripheral blood mononuclear cells (PBMC) to sacc was examined using a proliferation assay measuring uptake of tritiated thymidine. Cells from normal controls demonstrated dose-dependent proliferation, the time-course of which resembled that obtained with known recall antigens. Following separation of cell populations by rosetting with sheep erythrocytes, the responding cells were shown to be T-lymphocytes and the magnitude of the response was sensitive to the number of antigen-presenting cells present in the culture. When positive selection with immunomagnetic beads was used to further separate T-cells into highly purified CD4+ and CD8+ populations, responsiveness to yeast co-separated with the CD4+ subset. Following negative selection of cells expressing CD45RO or CD45RA, responsiveness was largely, but not exclusively, confined to the CD45RO+ population. Limiting dilution analysis of peripheral blood T-cells gave estimates of the sacc-specific precursor cell frequency in keeping with values previously reported for recall antigens, although the experimental data could not be shown to conform to single-hit kinetics. By sequential stimulation in long term culture, it was possible to obtain populations of cells which were uniquely responsive to sacc but unresponsive to other recall antigens. At some concentrations of sacc, proliferation responses of PBMC from Crohn's disease patients were higher than those in normal subjects, but the difference was not convincing overall. Digestion of sacc with pronase abolished the T-cell response but left specific antibody-binding intact, supporting the suggestion that antibody recognition is dependent on carbohydrate epitopes. Yeast cell wall mannan is implicated as the likely site of B-cell epitopes; evidence pertaining to T-cell epitopes is less conclusive. Thus, this study provides evidence that immune sensitisation to a common dietary constituent frequently occurs in the normal population, leading to detectable humoral and cellular immune responses. The T-cell response appears to be genuinely antigen-specific, and not due to non-specific lymphocyte activation. The gastrointestinal lymphoid system may be the site at which primary sensitisation occurs. In patients with Crohn's disease, the humoral response is enhanced, possibly as a consequence of inflammatory processes in the small bowel

Farmacoeconomia de anfotericina B complexo lipídico em pacientes com meningite criptocócica infectados pelo vírus da imunodeficiência humana em um hospital público de Curitiba

Orientador : Prof. Dr. Felipe Francisco Bondan TuonDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Medicina Interna. Defesa : Curitiba, 08/08/2017Inclui referências : f. 45-53Resumo: Introdução: Infecções fúngicas invasivas são complicações em pacientes imunocomprometidos. Em pacientes infectados pelo HIV, a meningite criptococócica é uma infecção oportunista importante com alta mortalidade. O tratamento de escolha inclui a anfotericina B, a qual pode ser utilizada na formulação desoxicolato ou nas formulações lipídicas. O desoxicolato de anfotericina B (d-AMB) tem uma taxa mais elevada de lesão renal aguda (LRA) em comparação com as formulações lipídicas, no entanto, o preço elevado das anfotericinas B lipídicas torna estas drogas opções não viáveis nos países em desenvolvimento. Objetivo: Determinar os gastos hospitalares diretos e indiretos d-AMB em pacientes com HIV com meningite criptocóccica e realizar uma simulação comparativa com a anfotericina B complexo lipídico (ABLC). Método: Este é um estudo retrospectivo, observacional, tipo coorte econômica. A análise de custo foi baseada no custo direto da d-AMB e hemodiálise (HD) aguda. A LRA foi classificada de acordo com os critérios de AKIN, avaliada até 24 h após o término da terapia ou morte. Os custos da HD crônica foram simulados, considerando dados da literatura de pacientes com LRA que evoluiram para insuficiência renal crônica dialítica. A análise realizada em nosso modelo foi de 10 anos, devido a sobrevivência após este tempo não ser previsível. Uma análise secundária foi realizada considerando a simulação do uso de ABLC somente após disfunção renal de acordo com a classificação de AKIN em pacientes sob terapia com d-AMB. Neste cálculo foram incluídos além dos custos da HD, os gastos com aposentadoria e da medicação. Foi realizada análise de sensibilidade e de equilíbrio dos custos de droga versus custos totais de HD. Resultados: De 102 pacientes tratados com d-AMB, 50% desenvolveram algum grau de LRA sem a necessidade de HD e 10,78% desenvolveram LRA grau 3 exigindo HD. A sobrevivência destes pacientes foi de 60%. De acordo com a literatura 37% dos pacientes que necessitam de HD aguda irão progredir para HD crônica, neste estudo a percentagem de pacientes com criptococose meníngea tratados com d-AMB sob HD crônica seria 2,39%. O mesmo modelo foi realizado simulando o uso com ABLC, resultou em 0,66% dos pacientes que necessitariam de HD crônica devido a sua menor nefrotoxicidade. O custo direto do tratamento da meningite criptocócica, considerandose apenas a terapêutica antifúngica foi menor em d-AMB 1mg/kg que ABLC 5mg/kg (R$1.820,00 versus R$ 53.760,00) para um paciente em tratamento (mediana de 14 dias). Considerando-se apenas os custos diretos de HD crônica para pacientes que desenvolveriam insuficiência renal crônica após a disfunção aguda e a taxa de sobrevivência esperada para esse grupo de pacientes, os custos totais seriam R$634.323,00 para d-AMB R$ 54.050,00 para ABLC. Em uma análise secundária foi considerado o uso de ABLC, realizando a troca precoce de d-AMB para ABLC somente após LRA com a classificação AKIN ?2. Neste modelo os custos totais com ABLC (medicação, hemodiálise e aposentadoria) seriam de R$982.811,00. A mudança de d- AMB para ABLC, nestas condições, faz com que o custo total com ABLC seja semelhante com d-AMB considerando 25$ 990.499,00 para d- AMB). Conclusão: Em um país em desenvolvimento como o Brasil, ABLC pode ser custo-efetivo em pacientes infectados pelo HIV com meningite criptocócica apenas se utilizado em insuficiência renal aguda precoce. Palavras chave: Anfotericina B; insuficiência renal; lesão renal aguda; cryptococcus; custo-efetividade.Abstract: Background: Invasive fungal infections are complications in immunocompromised patients. In HIV-infected patients, cryptococcal meningitis is an important opportunistic infection with high mortality. The treatment of choice includes amphotericin B, which can be used in the deoxycholate or different lipid formulations. The deoxycholate amphotericin B (d-AMB) has a higher rate of acute kidney failure (AKI) in comparison of lipid formulations, however high costs of lipid amphotericin B may turn them in a not viable option in developing countries. Objective: To determine the direct and indirect hospital costs of d-AMB in patients with cryptococcal meningitis and to perform a comparative simulation with the amphotericin B lipid complex (ABLC). Methods: This is a retrospective, observational, economic cohort study. The cost analysis was based on the direct cost of d-AMB and acute hemodialysis (HD). The AKI was classified according to the AKIN criteria, evaluated up to 24 h after termination of therapy or death. The costs of chronic HD were simulated, considering data from the literature of patients with AKI that progressed to chronic renal dialysis. An analysis performed on our 10 year model, due to a survival after that time, is not predictable. A secondary analysis was performed considering a simulation of the use of ABLC only after renal discrimination according to a classification of AKIN in patients undergoing d-AMB therapy. In this calculation, include HD, retirement, and drug costs. We performed a sensitivity and balance analysis of drug costs versus total HD costs. Results: Of 102 patients treated with d-AMB, 50% developed some degree of AKI without the need for HD and 10.78% developed AKI grade 3 requiring HD. The survival of these patients was 60%. According to the literature, 37% of patients who require acute HD will progress to chronic HD, in this study the percentage of patients with meningeal cryptococcosis treated with d-AMB under chronic HD would be 2.39%. The same model was performed simulating the use with ABLC, resulting in 0.66% of the patients who would need chronic HD due to their lower nephrotoxicity. The direct cost of treating cryptococcal meningitis, considering only antifungal therapy, was lower in d-AMB 1mg/kg than ABLC 5mg/kg (R$1,820.00 versus R$ 53,760.00) for a patient undergoing treatment (median of 14 days). Considering only the direct costs of chronic dialysis for patients who would develop chronic renal failure after acute dysfunction and the expected survival rate for this group of patients, the total costs would be R $634,323.00 for d-AMB R$ 54,050.00 for ABLC. In a secondary analysis the use of ABLC was considered, performing the early exchange of d-AMB for ABLC only after AKI with AKIN ?2. In this model, the total costs with ABLC (medication, hemodialysis and retirement) would be R $982,811.00. The change from d-AMB to ABLC under these conditions causes the total cost with ABLC to be similar with d-AMB considering 25$ 990,499.00 for d-AMB). Conclusions: In a developing country like Brazil, ABLC may be cost-effective in HIVinfected patients with cryptococcal meningitis only if used in early acute renal failure. Keywords: Amphotericin B; renal failure; acute kidney injury; cryptococcus; costeffectiveness

Evidence-Based Guidelines for Empirical Therapy of Neutropenic Fever in Korea

Neutrophils play an important role in immunological function. Neutropenic patients are vulnerable to infection, and except fever is present, inflammatory reactions are scarce in many cases. Additionally, because infections can worsen rapidly, early evaluation and treatments are especially important in febrile neutropenic patients. In cases in which febrile neutropenia is anticipated due to anticancer chemotherapy, antibiotic prophylaxis can be used, based on the risk of infection. Antifungal prophylaxis may also be considered if long-term neutropenia or mucosal damage is expected. When fever is observed in patients suspected to have neutropenia, an adequate physical examination and blood and sputum cultures should be performed. Initial antibiotics should be chosen by considering the risk of complications following the infection; if the risk is low, oral antibiotics can be used. For initial intravenous antibiotics, monotherapy with a broad-spectrum antibiotic or combination therapy with two antibiotics is recommended. At 3-5 days after beginning the initial antibiotic therapy, the condition of the patient is assessed again to determine whether the fever has subsided or symptoms have worsened. If the patient's condition has improved, intravenous antibiotics can be replaced with oral antibiotics; if the condition has deteriorated, a change of antibiotics or addition of antifungal agents should be considered. If the causative microorganism is identified, initial antimicrobial or antifungal agents should be changed accordingly. When the cause is not detected, the initial agents should continue to be used until the neutrophil count recovers