The Use of Amphotericin B in Nosocomial Fungal Infection

Aspergillus species are increasingly recognized as major fungal pathogens in severely immunosuppressed or neutropenic patients (8,9,20,22,51,62,71,81,82,103,107, 112). As organ transplantations and aggressive antineoplastic chemotherapy regimens are becoming more frequent, increasing numbers of patients will be susceptible to an Aspergillus infection. Moreover, patients with AIDS probably have a higher incidence ofAspergillus infections than immunocompetent individuals (21). In the immunosuppressed or neutropenic host, invasive pulmonary aspergillosis (IPA), characterized by hyphal invasion and destruction of pulmonary tissue, is the most common manifestation of an Aspergillus infection, although local infections also occur in the sinuses, the skin, or intravenous catheters (1,8,9,20,82,89,101). Dissemination from these initial ports of entry to other organs can be a secondary event in about 20% or more of the cases (1,8,9,20,22,82,101). Aspergillus fumigatus, A. flavus, A. niger, and A. terreus strains were the most frequently observed strains in cases of documented infection (105).Aspergilli are respiratory pathogens, and pulmonary infections are usually acquired through the inhalation ofAspergillus conidia, which are universally present in unfiltered air (9,73,81,103). With a diameter of about 2.5 to 3.5 ,um, these conidia are able to reach small airways and the alveolar space, where the impaired host defense mechanisms allow hyphal germination of the aspergilli and subsequent tissue invasion (9,44,83,103,105). Some patients, however, may have Aspergillus colonization of the nasal sinuses and endogenous spread to the lungs, causing IPA (9, 89, 101). In these latter cases, the exact pathomechanisms of IPA manifestation and the way in which it disseminates from the sinuses to the lungs are less clear.The true incidence of IPA in susceptible patients is not known. In two relatively recent autopsy series, IPA was documented in about 10% of patients with hematological malignancies (8,20). In many cases the condition was not suspected clinically (20). Clinical reports show that the incidence of IPA differs greatly worldwide, at different treatment centers and even within the same institution, ranging from as low as 0% to 25% or more (8,9,28,62,82,88,103 (9,62,73,88). Spore counts in the hospital environment depend on the location and type of building and the type of air filtration used at the time the samples were taken. Without air filtration, spore counts of 5.0/m3 probably do not differ from outdoor samples, whereas by using high-efficiency particulate air (HEPA) filtration, concentrations of spores as low as 0.009/m3 can be achieved (73,88). Aspergillus infections occur more frequently when the spore counts are high. Numerous reports describe microepidemics of IPA coinciding with construction activity or with defective ventilation systems, and variable counts of 2.3 to 5.9 spores per m3 have been measured at these locations (9,72,73,81,88,103). A patient's susceptibility to anAspey*llus infection is determined ...

Section: )mentioning

confidence: 99%

Section: )mentioning

confidence: 99%

Strategies in prevention of invasive pulmonary aspergillosis in immunosuppressed or neutropenic patients

Beyer

Schwartz

Heinemann

et al. 1994

“…A triazole antifungal agent, fluconazole (Flu), is fungistatic only against fungi susceptible to this agent (16,27). A polyene antifungal antibiotic, amphotericin B (AmB), remains the drug of choice, although its severe adverse effects such as nephrotoxicity are a dose-limiting factor (9,20). A great deal of experimental and clinical effort with the aim of increasing antifungal activities while reducing adverse effects has been made for the last two decades.…”

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confidence: 99%

In vitro and in vivo antifungal activities of DU-6859a, a fluoroquinolone, in combination with amphotericin B and fluconazole against pathogenic fungi

Nakajima¹,

Kitamura²,

Someya³

et al. 1995

DU-6859a is an investigational fluoroquinolone agent with potent bactericidal activity, but by itself it has no antifungal activity. When combined with amphotericin B (AmB), however, DU-6859a clearly enhanced the in vitro antifungal activity of AmB against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, and Cryptococcus neoformans in microdilution checkerboard studies. Positive interactions of DU-6859a with AmB against Aspergillus fumigatus were dependent on the medium used; yeast nitrogen base supplemented with amino acids, ammonium sulfate, and 1% glucose was better for demonstrating synergism, while in RPMI 1640 medium, unexpected antagonism between the drugs occurred against three of the strains tested. In combination with fluconazole (Flu), DU-6859a increased the activity of Flu against C. albicans both in synthetic amino acid medium fungal and in supplemented yeast nitrogen base. An in vitro time-kill study revealed that DU-6859a combined with AmB significantly suppressed the regrowth of C. albicans compared with the suppression brought about by AmB used alone in a concentration-dependent fashion. Furthermore, in a model of C. albicans infection in mice, the fungal load in infected kidneys was significantly less in mice given the combination treatment of DU-6859a plus either AmB or Flu, and thus, the combination treatment resulted in prolonged survival of infected mice compared with treatment with either antifungal alone. The prolonged survival in mice given the combined treatment was also observed in mice with A. fumigatus infection, indicating that DU-6859a potentiated the actions of the antifungal agents in vivo as well as in vitro.In patients with immune deficiencies induced both iatrogenically and congenitally or by human immunodeficiency virus infection, deep-seated mycoses caused by Candida species, Aspergillus species, and Cryptococcus neoformans occur frequently and often become life-threatening (1,3,4,29). A triazole antifungal agent, fluconazole (Flu), is fungistatic only against fungi susceptible to this agent (16,27). A polyene antifungal antibiotic, amphotericin B (AmB), remains the drug of choice, although its severe adverse effects such as nephrotoxicity are a dose-limiting factor (9,20). A great deal of experimental and clinical effort with the aim of increasing antifungal activities while reducing adverse effects has been made for the last two decades. These efforts include the combined use of two distinct antimicrobial agents: AmB plus flucytosine, a cytosine analog (2, 18), AmB plus rifampin (15, 18), and azoles plus nikkomycin, a competitive fungal chitin synthase inhibitor (11).It has been verified that DU-6859a, a fluoroquinolone agent, possesses a broad spectrum of potent bactericidal activity (14,22), but by itself it has no antifungal activity. The bactericidal activities of fluoroquinolones are largely based on their inhibitory effects on bacterial DNA gyrase (topoisomerase II) (23, 24); however, some other effects have recently been suggested (7, 13). The...

“…(i) Fluconazole and 5-fluorocytosine each failed to inhibit pseudohyphal formation and cell aggregation even when applied at 10 and 50 ,ug/ml, respectively, for up to 10 h. Hence, these agents were not fungistatic when tested in the presence of serum. Amphotericin B, fluconazole, and 5-fluorocytosine are presently the drugs most commonly used for treating systemic infections with Candida albicans (3,13,18,22,28,32,39). Although the rnodes of action and pharmacokinetic properties of all three agents have been well studied (1, 3, 7, 21, 38, 46, 50), consensus regarding their application alone or in combination with each other is only slowly being reached.…”

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confidence: 99%

Antagonistic effects of fluconazole and 5-fluorocytosine on candidacidal action of amphotericin B in human serum

Martin¹,

Maier²,

Bhakdi³

1994

This study addressed the effects of fluconazole and 5-fluorocytosine on the candidacidal activity of amphotericin B in the presence of human serum. A Candida albicans isolate that was susceptible to all three agents according to standard testing procedures was employed. Fungicidal activity was estimated by using a flow cytometric procedure that exploited the fact that yeast cells killed by amphotericin B diminish in size and take up propidium iodide. The following findings were made. (i) Fluconazole and 5-fluorocytosine each failed to inhibit pseudohyphal formation and cell aggregation even when applied at 10 and 50 ,ug/ml, respectively, for up to 10 h. Hence, these agents were not fungistatic when tested in the presence of serum. Amphotericin B, fluconazole, and 5-fluorocytosine are presently the drugs most commonly used for treating systemic infections with Candida albicans (3,13,18,22,28,32,39). Although the rnodes of action and pharmacokinetic properties of all three agents have been well studied (1, 3, 7, 21, 38, 46, 50), consensus regarding their application alone or in combination with each other is only slowly being reached. One reason for this is the difficulty in assessing the fungistatic and fungicidal activities of these agents in vitro and in vivo. Results of in vitro susceptibility tests for each agent depend heavily on many factors that must be heeded, such as composition of the medium, pH, temperature, and size of inoculum, in order for reproducible data to be obtained (15,37). Attempts to test combinations therefore encounter formidable obstacles. Furthermore, the activity of antifungal agents is almost always assessed in the absence of serum. Serum is avoided because it strongly promotes formation of pseudohyphae and cell aggregation, processes that severely impede accurate determinations of numbers of viable cells. On the other hand, systemically applied agents must perform in vivo in the presence of serum constituents and other proteins, so assessment of the activity of the agents under such conditions may not be trivial. This point has been readdressed by van Etten et al. in a recent publication (47). Amphotericin B exhibits a high degree of binding to serum components (1,(3)(4)(5), and the antifungal activity of this agent in whole serum is reduced by an order of magnitude (9,30,47). In contrast, the degree of binding of fluconazole and 5-fluorocytosine to serum components is low (7,21,46,49), and it is therefore generally assumed that results of susceptibility tests in protein-free media can be extrapolated to the situation in which serum is present. However, we are not aware of any study that has directly investigated the fungistatic effect of either fluconazole or 5-fluorocytosine on C. albicans in serum.In a previous communication, we ric assay for measuring the candidacidal activity of amphotericin B in whole human serum (25). The assay exploited the facts that C. albicans cells damaged by amphotericin B and treated with deoxycholate take up the marker dye propidium iodide, which ...