A Review of Complications of Amphotericin-B Therapy: Recommendations for Prevention and Management

Maddux, Michael S.; Barriere, Steven L.

doi:10.1177/106002808001400303

Cited by 95 publications

(44 citation statements)

References 41 publications

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“…An additional problem occurs with fungal infections in severely immunocompromised patients, such as those with the acquired immunodeficiency syndrome; cure is unlikely, and lifelong maintenance therapy may therefore be required to prevent relapse. Clinical use of AmB is also limited by the frequent toxic reactions (35). Nephrotoxicity is ultimately the dose-limiting factor in many patients, particularly when AmB is used in combination with other potentially nephrotoxic agents (aminoglycosides, cyclosporins, etc.…”

Section: Problems With the Use Of Ambmentioning

confidence: 99%

Amphotericin B: current understanding of mechanisms of action

Brajtburg

Powderly

Kobayashi

et al. 1990

Antimicrob Agents Chemother

479

263

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Section: Problems With the Use Of Ambmentioning

confidence: 99%

Amphotericin B: current understanding of mechanisms of action

Brajtburg

Powderly

Kobayashi

et al. 1990

Antimicrob Agents Chemother

479

263

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“…Early empirical treatment with antifungal drugs, such as amphotericin B (AmB), reduces the mortality rate. However, AmB is considered highly nephrotoxic (18) and has often been found inadequate for complete elimination of the infection in the immunosuppressed subjects. Because invasive aspergillosis is extremely rare in immunocompetent individuals, therapy aimed at strengthening the host's immune response to the organisms offers a promising new approach in the treatment of this disease.…”

mentioning

confidence: 99%

Protective Role of Lung Surfactant Protein D in a Murine Model of Invasive Pulmonary Aspergillosis

et al. 2001

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Aspergillus spp. are increasingly recognized as major fungal pathogens in immunocompromised or neutropenic patients, and Aspergillus fumigatus is responsible for nearly 90% of cases of invasive pulmonary aspergillosis (IPA) (7). As the incidence of AIDS, aplastic anemia, and organ transplantation increases and the use of chronic glucocorticoid treatment and aggressive antineoplastic chemotherapy regimes becomes more frequent, the number of patients susceptible to Aspergillus infection is rising. In immunocompromised or neutropenic patients, IPA, the most common form of the disease, is characterized by hyphal invasion and destruction of pulmonary tissue. Dissemination of Aspergillus infection to other organs occurs in approximately 20% of IPA cases (4). In spite of correct diagnosis and treatment, IPA results in patient mortality of greater than 80%. The mortality rate among bone marrow transplantation patients can be as high as 95% (26). Early empirical treatment with antifungal drugs, such as amphotericin B (AmB), reduces the mortality rate. However, AmB is considered highly nephrotoxic (18) and has often been found inadequate for complete elimination of the infection in the immunosuppressed subjects. Because invasive aspergillosis is extremely rare in immunocompetent individuals, therapy aimed at strengthening the host's immune response to the organisms offers a promising new approach in the treatment of this disease.Host defense against Aspergillus infections is considered to be mediated by macrophages, neutrophils, and polymorphonuclear cells (PMNs) (6,16,23,24,25,28). The respiratory tract appears to be the portal of entry in most cases of IPA (3). Therefore, there has been an extensive search for molecules in the lung which can selectively enhance the contribution of the innate immune mechanism of phagocytes against Aspergillus infection. Lung surfactant proteins SP-A and SP-D have potent chemotactic activity for various subsets of mononuclear leukocytes and have been shown to enhance phagocytosis and production of superoxide anion by macrophages and neutrophils (29). SP-A and SP-D, which belong to a family of proteins called collectins, are also known to interact with carbohydrate structures present on the surfaces of a wide range of pathogens, such as viruses, bacteria, and fungi, via their carbohydrate recognition domains (CRDs) and to enhance phagocytosis and killing by neutrophils and macrophages (22,29). Collectins are composed of subunits, each of which contains a collagen-like triple-helical region, followed by an ␣-helical, trimerizing neck region and three CRDs at its C-terminal end. Six of these trimeric subunits make up the overall structure of SP-A, while SP-D is composed of a cruciform structure with four arms of equal lengths (10). Mice deficient in SP-A were observed to be less effective in clearing Staphylococcus aureus and Pseudomonas aeruginosa and were more susceptible to lung inflammation and splenic dissemination of group B streptococci (13-15).We have previously shown that SP-A and S...

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“…There are a number of side effects observed with AmB treatment, including fever, chills, thrombophlebitis, anemia, and nephrotoxicity (5,21). The inflammatory action of AmB on leukocyte function could contribute to the toxicity of AmB both by direct action on PMN function and by indirect mechanisms through the expression and release of endogenous mediators.…”

mentioning

confidence: 99%

Lipid complexing decreases amphotericin B inflammatory activation of human neutrophils compared with that of a desoxycholate-suspended preparation of amphotericin B (Fungizone)

Sullivan

Carper

Mandell

1992

Antimicrob Agents Chemother

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Amphotericin B (AmB) has toxic effects and alters neutrophil (polymorphonuclear leukocyte [PMN]) function. A lipid-complexed formulation of AmB (AmB-LC) has been reported (A. S. Janoff, L. T. Boni, M. C. Popescu, S. R. Minchey, P. R. Cuilis, T. D. Madden, T. Taraschi, S. M. Gruner, E. Shyamsunder, M. W. Tate, R. Mendelsohn, and D. Bonner, Proc. Natl. Acad. Sci. USA 85:6122-6126, 1988) to be less toxic than a desoxycholate-suspended preparation of AmB (AmB-des; Fungizone). In this study we compared the effects of AmB-des and AmB-LC on in vitro PMN function. Neither form of AmB stimulated PMN chemiluminescence, but AmB-des (2 ,ug/mI) nearly tripled PMN chemiluminescence in response to f-Met-Leu-Phe (fMLP), a phenomenon known as priming. Because AmB stimulates monocytes to release cytokines which can affect PMN function, we studied the effects of AmB on PMNs in mixed leukocyte cultures. AmB-des (1 to 2 ,ug/ml) increased the chemiluminescence of PMNs plus mixed mononuclear leukocytes (MNLs) to fMLP. The activity was about three times that of PMNs plus MNLs and seven times the activity of PMNs stimulated with fMLP in the absence of MNLs. Cell-free AmB-des (2 ,ug/ml)-stimulated, MNL-conditioned medium primed pure PMNs to a level equal to that of whole MNLs treated with AmB-des. AmB-LC was much less potent. AmB-LC (20 ,ug/ml) increased fMLP-stimulated chemiluminescence to two times that of PMNs plus MNLs without AmB-LC. AmB-des (2 ,ug/ml) (but not AmB-LC [2 ,ug/ml]) increased nitroblue tetrazolium reduction by PMNs in whole blood from 31 to 52% of positive cells. Neither form of AmB increased Mac-1 (the CD11b/CD18 integrin) expression of pure PMNs. AmB-des (0.5 to 2 ,ug/ml) (but not AmB-LC [c40 ,ug/ml]) nearly doubled PMN Mac-1 expression in the presence of MNLs, and cell-free AmB.des (2 ,ug/ml)-stimulated, MNL-conditioned medium stimulated PMN Mac-i to l25% of the control level. AmB-des (0.2 to 2 ,ug/ml) (but not AmB-LC [.40 jg/ml]) decreased chemotaxis of pure PMNs to fMLP by as much as 35% and that of PMNs in the presence of MNLs by as much as 50%. l)esoxycholate by itself had no effect on PMN function. These differences in activity between AmB-des and AmB-LC may explain the lessened toxicity observed with AmB-LC.Amphotericin B (AmB) is a widely used antifungal agent. In several laboratories (3,9,18,22,33,37) it has been observed that in vitro neutrophil (polymorphonuclear leukocyte [PMN]) function is altered by AmB. Other laboratories have reported that AmB affects macrophage function (6,17,27,36) and stimulates monokine production from both human and murine cells (8,14). Because both tumor necrosis factor-a (TNF-a) and interleukin-lp (IL-1p) have inflammatory actions on PMN function, we hypothesized that the increased expression of these monokines might exacerbate the effects of AmB on PMN function. We found that the presence of mononuclear leukocytes (MNLs) increases the effects of AmB on PMN function.There are a number of side effects observed with AmB treatment, including fever, chills, thrombophlebitis, anemi...

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A Review of Complications of Amphotericin-B Therapy: Recommendations for Prevention and Management

Cited by 95 publications

References 41 publications

Amphotericin B: current understanding of mechanisms of action

Amphotericin B: current understanding of mechanisms of action

Protective Role of Lung Surfactant Protein D in a Murine Model of Invasive Pulmonary Aspergillosis

Lipid complexing decreases amphotericin B inflammatory activation of human neutrophils compared with that of a desoxycholate-suspended preparation of amphotericin B (Fungizone)

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