Infections with fluconazole-resistant Candida albicans isolate have rarely been described in clinical settings other than oropharyngeal candidiasis in patients with late-stage AIDS. We report on two patients with leukemia who developed fungemia caused by fluconazole-resistant C. albicans after receiving fluconazole prophylaxis (400 mg/day) and empiric amphotericin B therapy (0.5 mg/kg of body weight per day). The fluconazole MICs for the isolates were > or = 64 micrograms/ml, and the isolates were resistant to other azoles and had membrane sterol changes consistent with a mutation in the delta 5,6-sterol desaturase gene. The lack of ergosterol in the cytoplasmic membrane of the fluconazole-resistant strains also imparted resistance to amphotericin B. Both patients were successfully treated with high-dose amphotericin B (1 to 1.25 mg/kg/day) and flucytosine (150 mg/kg/day).
A series of 23 monoclonal antibodies reactive with normal lymphoid and myeloid cells at various stages of differentiation were used to characterize 96 adult patients with acute myelocytic leukaemia (AML), concentrating on the possible role the expression of these antigens may have in predicting response to intensive chemotherapy. Only the expression of CD34 (P = 0.008) and HLA-DR (P = 0.035) was significant in predicting response to therapy; patients with leukaemic cells expressing CD34 (My10) had a complete remission (CR) rate of 59% compared to 87% for those with blasts not expressing the antigen. In a multivariate analysis predicting for CR, the expression of CD34, the disease category (de novo AML versus secondary AML [SAML] or a history of antecedent haematological disorder [AHD]), and WBC were significant covariates. Adjusting for disease category and WBC, patients with CD34-positive AML were one-third as likely to enter CR as with those with disease not expressing the antigen (P = 0.066). Comparison of clinical characteristics between the 58 patients whose leukaemia expressed CD34 and the 33 which were CD34-negative found that patients with CD34-positive AML had a higher incidence of SAML and AHD, a lower WBC at diagnosis, and a more frequent incidence of chromosomal abnormalities involving chromosomes 5 and/or 7. Twenty-eight of these patients also had immunophenotyping performed at relapse. Patients who presented with CD34-positive AML, and entered remission, and then relapsed all recurred with CD34-positive leukaemia; there was no case of CD34-positive AML at diagnosis relapsing with CD34-negative disease. In addition, there were patients presenting with CD34-negative AML and then relapsing with CD34-positive AML. These results suggest that intensive cytoreductive therapy is ineffective against CD34-positive AML. Patients who present with CD34-positive AML may require different therapeutic approaches to completely eradicate their disease.
The purpose of this open-label, prospective study was to compare steady state concentrations and clearances of intravenously administered cyclosporine or tacrolimus with and without concomitant high-dose (400 mg/day) fluconazole in allogeneic BMT patients. Twenty-one patients were evaluable. The mean steady state cyclosporine and tacrolimus concentrations without fluconazole were 320.3 and 18.2 ng/ml and increased to 389.2 and 21.2 ng/ml, respectively, after the addition of fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) increase. The mean steady state clearance of cyclosporine and tacrolimus without fluconazole was 6.82 and 1.28 ml/min/kg, which decreased to 5.57 and 1.10 ml/min/kg with fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) decrease, respectively. The 21% difference in the cyclosporine concentration and clearance was not thought to be clinically significant. These results suggest that fluconazole's interaction with cyclosporine or tacrolimus may be a result of fluconazole's inhibition of gut metabolism, resulting in a greater extent of absorption.
Summary
In paroxysmal nocturnal haemoglobinuria (PNH), chronic destruction of PNH red blood cells (RBCs) by complement leads to anaemia and other serious morbidities. Eculizumab inhibits terminal complement‐mediated PNH RBC destruction by targeting C5. In the phase III, double‐blind, placebo‐controlled, TRIUMPH study, eculizumab reduced haemolysis, stabilized haemoglobin levels, reduced transfusion requirements and improved fatigue in patients with PNH. Herein, we explored the effects of eculizumab on measures of anaemia in patients from the TRIUMPH study and the open‐label SHEPHERD study, a more heterogeneous population. Eculizumab reduced haemolysis regardless of pretreatment transfusion requirements and regardless of whether or not patients became transfusion‐dependent during treatment (P < 0·001). Reduction in haemolysis was associated with increased PNH RBC counts (P < 0·001) while reticulocyte counts remained elevated. Eculizumab‐treated patients demonstrated significantly higher levels of haemoglobin as compared with placebo in TRIUMPH and relative to baseline levels in SHEPHERD (P < 0·001 for each study). Eculizumab lowered transfusion requirement across multiple pretreatment transfusion strata and eliminated transfusion support in a majority of both TRIUMPH and SHEPHERD patients (P < 0·001). Patients who required some transfusion support during treatment with eculizumab showed a reduction in haemolysis and transfusion requirements and an improvement in fatigue. Eculizumab reduces haemolysis and improves anaemia and fatigue, regardless of transfusion requirements.
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