Efficacy of oral amphotericin B in AIDS patients with thrush clinically resistant to fluconazole

Dewsnup, Daniel H.; Stevens, David A.

doi:10.1080/02681219480000511

Cited by 39 publications

(21 citation statements)

References 30 publications

(32 reference statements)

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“…Treatment of this infection has become more difficult in the past few years with the rising incidence of fluconazole-resistant strains of Candida albicans. Because of this rise in resistance, other treatments, such as oral amphotericin B, have been used (4). However, new therapeutic options are needed.…”

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confidence: 99%

Efficacy of Ravuconazole in Treatment of Mucosal Candidosis in SCID Mice

Clemons

Stevens

2001

Antimicrob Agents Chemother

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A model of orogastric candidosis in SCID mice, which mimics disease seen in AIDS patients, was used to evaluate ravuconazole in comparison with fluconazole for treatment. Mice were infected orally with Candida albicans and received either no treatment or oral treatment once daily for 12 days with 1, 5, or 25 mg of ravuconazole per kg of body weight per day, 5 or 25 mg of fluconazole per kg per day, or diluent (10% dimethyl sulfoxide in 0.5% carboxymethyl cellulose). The numbers of C. albicans CFU in the esophagus, stomach, small intestine, and cecum on day 25 in mice given no treatment and diluent were equivalent. Both doses of fluconazole significantly reduced numbers of CFU in all four tissues but were equivalent to each other. Ravuconazole showed dose-responsive improvement of clearance of CFU. Ravuconazole at 25 mg/kg was superior in reduction of numbers of CFU in all tissues to controls or 25 mg of fluconazole per kg and to other regimens in at least three tissues. Fluconazole at 25 mg/kg cured no infection in any tissue, whereas 25 mg of ravuconazole/kg cleared infection in all tissues from 50% of mice. Ravuconazole has good efficacy and the potential to cure mucosal candidosis in the absence of a functional immune response.Mucosal candidosis is often encountered in a variety of patient populations, particularly those that are immunocompromised. Among the most frequently infected persons are those with human immunodeficiency virus or AIDS (1). Treatment of this infection has become more difficult in the past few years with the rising incidence of fluconazole-resistant strains of Candida albicans. Because of this rise in resistance, other treatments, such as oral amphotericin B, have been used (4). However, new therapeutic options are needed.A murine model of persistent colonization of the gastrointestinal mucosa established in severe combined immunodeficient (SCID) mice has been described (2,3,8,12). This model closely mimics disease found in AIDS patients. The mucosal surfaces are heavily colonized, but systemic dissemination rarely occurs, in contrast to chemotherapy patients receiving agents, such as 5-fluorouracil or methotrexate, that damage the intestinal mucosa, allowing translocation of C. albicans and subsequent dissemination. Because of the similarity to human infection in AIDS patients, the model is useful for the study of new antifungal agents.Ravuconazole (BMS207147) is a novel triazole currently under development by Bristol-Myers Squibb (Princeton, N.J.) (7). This azole has been shown to have both in vitro and in vivo efficacy against several fungal genera (6, 7, 10, 11, 14, 15). In vitro, ravuconazole has been shown to have good activity against fluconazole-or itraconazole-resistant isolates of C. albicans and Candida dubliniensis (14, 15). Ravuconazole has recently been shown to have good in vitro activity against the endemic pathogens and was lethal at concentrations at or near the MIC (D. A. Stevens, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1514, 1999). In additio...

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Efficacy of Ravuconazole in Treatment of Mucosal Candidosis in SCID Mice

Clemons

Stevens

2001

Antimicrob Agents Chemother

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“…Several reports indicate that itraconazole is an effective alternative for fluconazole-resistant candidosis (Dupont et al, 1996;Phillips et al, 1996;Cartledge et al, 1997). Amphotericin B used orally, intravenously, or liposomally may also be effective (Dewsnup and Stevens, 1994;Nguyen et al, 1996).…”

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Oral Candidal Infections and Antimycotics

Ellepola

Samaranayake

2000

Critical Reviews in Oral Biology & Medicine

209

236

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The advent of the human immunodeficiency virus infection and the increasing prevalence of compromised individuals in the community due to modern therapeutic advances have resulted in a resurgence of opportunistic infections, including oral candidoses. One form of the latter presents classically as a white lesion of "thrush" and is usually easily diagnosed and cured. Nonetheless, a minority of these lesions appears in new guises such as erythematous candidosis, thereby confounding the unwary clinician and complicating its management. Despite the availability of several effective antimycotics for the treatment of oral candidoses, failure of therapy is not uncommon due to the unique environment of the oral cavity, where the flushing effect of saliva and the cleansing action of the oral musculature tend to reduce the drug concentration to sub-therapeutic levels. This problem has been partly circumvented by the introduction of the triazole agents, which initially appeared to be highly effective. However, an alarming increase of organisms resistant to the triazoles has been reported recently. In this review, an overview of clinical manifestations of oral candidoses and recent advances in antimycotic therapy is given, together with newer concepts, such as the post-antifungal effect (PAFE) and its possible therapeutic implications.

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“…Reports from medical centers caring for human immunodeficiency virus (HIV)-seropositive patients during the past two decades have shown an increasing prevalence of recalcitrant oropharyngeal and vaginal candidiasis that for the most part has resulted from antimicrobial agent-resistant Candida species, including C. glabrata (5,7,8,29). The high frequencies of in vitro resistance to fluconazole (MIC 90 s Ͼ 64.0 g/ml) and itraconazole (MIC 90 s ϭ 4.0 g/ml) among C. glabrata organisms isolated from patients at a hospital with a substantial population of HIV-infected individuals (center III) were significant in our study (P Ͻ 0.001) ( Table 2).…”

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Prospective, Multicenter Surveillance Study of Candida glabrata : Fluconazole and Itraconazole Susceptibility Profiles in Bloodstream, Invasive, and Colonizing Strains and Differences between Isolates from Three Urban Teaching Hospitals in New York City ( Candida Susceptibility Trends Study, 1998 to 1999)

Safdar

Chaturvedi

Koll³

et al. 2002

Antimicrob Agents Chemother

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Since the 1990s, the substantial increase in the rate of Candida glabrata infections has become a serious problem. As most C. glabrata infections arise from the host's endogenous microflora, the present prospective, multicenter analysis included all clinical isolates associated with colonization and with systemic and hematogenous candidiasis. Among 347 C. glabrata isolates, the overall rates of resistance to fluconazole (MIC > 64 g/ ml) and itraconazole (MIC > 1 g/ml) were 10.7 and 15.2%, respectively, although for half (n ‫؍‬ 148) of the itraconazole-susceptible isolates the MICs (0.25 to 0.5 g/ml) were in the susceptible-dependent upon dose range. Fluconazole resistance was more common among C. glabrata isolates obtained from centers caring for patients with cancer (MICs at which 90% of isolates are inhibited [MIC 90 s] ‫؍‬ 32 g/ml) or AIDS (MIC 90 s > 64 g/ml) than among C. glabrata isolates from a community-based university medical center (MIC 90 s ‫؍‬ 16 g/ ml) (P ‫؍‬ 0.001). Thirty-three bloodstream isolates and those obtained from other body sites had similar in vitro susceptibility profiles. The fluconazole MIC 90 s (<16 g/ml) for C. glabrata yeast isolates from the gastrointestinal tract were lower than those (>64 g/ml) for C. glabrata isolates from respiratory and urinary tract samples (P ‫؍‬ 0.01). A similar discrepancy for itraconazole was not significant (P > 0.5). We did not observe differences in fluconazole or itraconazole susceptibility profiles among C. glabrata isolates associated with either hematogenous dissemination or colonization. The significant discrepancy in antifungal susceptibility among C. glabrata organisms isolated from hospitals in the same geographic region emphasizes the significance of periodic susceptibility surveillance programs for individual institutions, especially those providing care to patients at risk.

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Efficacy of oral amphotericin B in AIDS patients with thrush clinically resistant to fluconazole

Cited by 39 publications

References 30 publications

Efficacy of Ravuconazole in Treatment of Mucosal Candidosis in SCID Mice

Efficacy of Ravuconazole in Treatment of Mucosal Candidosis in SCID Mice

Oral Candidal Infections and Antimycotics

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