Glucocorticoid-Induced Impairment of Macrophage Antimicrobial Activity: Mechanisms and Dependence on the State of Activation

Experimental observations indicate that tissue macrophages deployed in great numbers at critical anatomic sites such as the liver, spleen, and lung are major targets for glucocorticoids compromising natural resistanceof the host. Therapeutic concentrations ofglucocorticoids appear to prevent destruction of microorganisms ingested by macrophages without interfering with phagocytosis, phagolysosomal fusion, and/or secretion of reactive oxygen intermediates. These findings indicate that at the cellular level the glucocorticoid target should be sought for in the nonoxidative armature of the phagocyte and that nonoxidative killing systems of resident tissue macrophages play an important role in natural resistance to opportunistic pathogens. Glucocorticoids do not prevent lymphokine-induced activation of oxidative killing systems. Thus, lymphokines such as interferon-γ can restore the microbicidal activity of macrophages functionally impaired by glucocorticoids. Counterbalance of the suppressive effect of glucocorticoids by lymphokines might only be possible, however, for pathogens susceptible to oxidative killing and not for microorganisms that are more resistant to reactive oxygen intermediates such as Aspergillus spores and Nocardia, opportunists that appear to be particularly associated with hypercortisolis

Effect of Prophylactic Fluconazole on the Frequency of Fungal Infections, Amphotericin B Use, and Health Care Costs in Patients Undergoing Intensive Chemotherapy for Hematologic Neoplasias

Fungal infections are a major problem in patients with hematologic malignancy. Attempts to reduce their frequency with antifungal agents have not been successful. A double-blind, controlled, single-center trial was conducted with 96 consecutive patients undergoing 154episodes of chemotherapy. Patients received 400 mg of fluconazole or placebo until bone marrow recovery or initiation of intravenous amphotericin B infusions. End points were amphotericin B use, fungal infection, stable neutrophil count >0.5 × 109/L, toxicity precluding further fluconazole use, and death. By KaplanMeier estimation, the time to initiation of amphotericin B therapy was shorter in 76 patients treated with placebo than in 75 treated with fluconazole (P = .003). Also, fluconazole reduced the number of febrile days by 20% (P = .002) and prevented oropharyngeal candidiasis (1/75 vs. 9/76, P = .018). The frequency of deep mycoses (8/76 vs. 8/75) and outcome were unaffected. Fluconazole did not have a favorable effect on infection-related health care costs and was associated with prolonged severe neutropenia (P = .01

Pretransplant Evaluation for Infections in Donors and Recipients of Solid Organs

The risk of infectious disease reactivation in recipients of and transmission by solid-organ transplants remains, and thorough screening and testing of recipient and donor is especially important. In conceiving screening strategies, it is crucial to consider the sensitivity and specificity of individual diagnostic tests in the context of their use. Furthermore, recognition of special risks for infectious complications of transplantation will help to guide preventive, diagnostic, and therapeutic steps in the control of infectious complications in individual patients. The acceptability of risks for infectious complications after transplantation depends also on the urgency of transplantation of a vital organ as well as the availability of organs. Although these principals are well accepted, standards for the extent of screening and criteria for inappropriate donors and exclusion of unfit recipients remain controversial to some exten

Comparison of the Activity of Free and Liposomal Amphotericin B In Vitro and in a Model of Systemic and Localized Murine Candidiasis

Because of the toxicity of amphotericin B-desoxycholate (AmB-d) during systemic therapy, less toxic forms of AmB, which promise to have a broader therapeutic index, are under investigation. There is, however, no convincing explanation of how such preparations might be made less toxic yet retain their antifungal efficacy. In this study, the antifungal activity of a less toxic, unilamellar liposomal (1) preparation of AmB (AmBisome), which is commercially available in some countries, was compared with conventional AmB-d in vitro and in models of systemic and localized candidiasis in immunosuppressed mice. Results indicate that 1AmB has four to eight times less antifungal activity than AmB-d in all experimental settings tested. Because 1AmB is significantly less active, the therapeutic index of such preparations must be tested clinically before their use can be recommended solely on the basis of toxicity dat