A Controlled Trial of Fluconazole or Amphotericin B to Prevent Relapse of Cryptococcal Meningitis in Patients with the Acquired Immunodeficiency Syndrome

Powderly, William G.; Saag, Michael S.; Cloud, Gretchen A.; Robinson, Patrick; Meyer, R D; Jacobson, Jeffrey M.; Graybill, John R.; Sugar, Alan M.; McAuliffe, Vincent J.; Follansbee, Stephen

doi:10.1056/nejm199203193261203

Cited by 331 publications

(107 citation statements)

References 15 publications

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“…However, there were more relapses among subjects receiving the triple combination after they had been switched to itraconazole alone. The results of other studies (162,171) have suggested that relapse rates among subjects with HIV-associated cryptococcal meningitis are higher with itraconazole as a secondary prophylaxis than with fluconazole. It should also be noted that the dose of amphotericin B used in this study was less than that recommended in Infectious Diseases Society of America guidelines (172).…”

Section: Neoformans (I) In Vitro Datamentioning

confidence: 96%

Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

486

368

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5 RATIONALEThe availability of new antifungal agents with novel mechanisms of action has stimulated renewed interest in combination antifungal therapies. In particular, and despite the limited clinical data, the high mortality of mold infections and the relatively limited efficacy of current agents have produced significant interest in polyene-, extended-spectrum azole-, and echinocandin-based combinations for these difficult-to-treat infections. With the recent publication of the first large randomized trial of antifungal combination therapy to be conducted in two decades (166) and the rapid proliferation of new in vitro and in vivo data on antifungal combinations, we have sought to review the recent work and future challenges in this area.The focus of this review is on the efficacy of antifungal drugs in combination with respect to the extent or rate of killing of the fungal pathogen, although other potential interactions (such as pharmacokinetic drug interactions) can impact efficacy when these agents are used together. The value of giving two drugs because each is separately effective against a group of organisms exhibiting a variety of types of resistance is not specifically discussed, but this also is an obvious and straightforward reason to use a combination of agents.It cannot be simply assumed that the use of two or more effective drugs with different mechanisms of action will produce an improved outcome compared to the results seen with a single agent. Combination antifungal therapy could reduce antifungal killing and clinical efficacy, increase potential for drug interactions and drug toxicities, and carry a much higher cost for antifungal drug expenditures without proven clinical benefit (106). Thus, it is important to critically evaluate the role of combination therapy as new data become available.Conceptual models and terminology. Methods for studying antifungal combinations in vitro and in vivo have differed considerably over time and among investigators. These tools do not differ with respect to their application to combination antibacterial or antiviral therapies and have been discussed extensively and elegantly in the landmark 1995 review by Greco (79). In brief, all approaches to evaluating combinations can be reduced to two elements: (i) a conceptual model for predicting the expected result for a combination and (ii) a set of phrases used to categorize results that are better than expected, worse than expected, or as expected. Although many subtle variations are possible, the underlying mathematical model is based on either the assumption of additive interactions or the assumption of probabilistic (multiplicative) interactions. On the basis of the terminology employed by the author who first carefully described each of these models, the two models can be usefully referred to as the Loewe additivity model and the Bliss independence model (79).The terminology used to place results into interpretive categories is often the subject of debate and confusion. Greco et al. (79) have proposed a set ...

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Section: Neoformans (I) In Vitro Datamentioning

confidence: 96%

Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

486

368

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“…However, an infection may occur along with T-cell defects or following a CD4-lymphocyte-depleting therapy. D-AmB (0.7-1 mg/kg) plus 5-flucytosine (100 mg/kg) for 2 weeks followed by maintenance therapy with fluconazole 400 mg/ day for 10 weeks is the recommended antifungal treatment of cryptococcal meningitis in HIV-infected patients (see Table 4) (AI) [5,8,38,84,95]. Data about AmB lipid formulations are limited.…”

Section: Cryptococcus Neoformans Infectionsmentioning

confidence: 99%

Treatment of invasive fungal infections in cancer patients—Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

Böhme¹,

et al. 2008

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International audienceInvasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. Early antifungal treatment is mandatory to improve survival. Today, a number of effective and better-tolerated but more expensive antifungal agents compared to the former gold standard amphotericin B deoxycholate are available. Clinical decision-making must consider results from numerous studies and published guidelines, as well as licensing status and cost pressure. New developments in antifungal prophylaxis improving survival rates result in a continuous need for actualization. The treatment options for invasive infections include fluconazole, voriconazole, and amphotericin B and its lipid formulations, as well as echinocandins. Voriconazole, amphotericin B, amphotericin B lipid formulations, caspofungin, itraconazole, and posaconazole are available for the treatment of invasive aspergillosis. Additional procedures, such as surgical interventions, immunoregulatory therapy, and granulocyte transfusions, have to be considered. The Infectious Diseases Working Party of the German Society of Hematology and Oncology here presents its 2008 recommendations discussing the dos and do-nots, as well as the problems and possible solutions, of evidence criteria selection

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“…Treatment by fluconazole of invasive infections due to various fungi has been a significant advance in antimicrobial chemotherapy (1,19,21). Its efficacy in treating cryptococcal and coccidioidal meningitis (2,3,5,14,22,23) is well established in clinical studies.In acute AIDS-associated cryptococcal meningitis fluconazole was shown to be as effective as amphotericin B (23) and more so in preventing relapse (3,22). However, use of fluconazole for treatment of this disease remains controversial (6,20,24), and the optimal dose remains uncertain.…”

mentioning

confidence: 99%

Fluconazole penetration in cerebral parenchyma in humans at steady state

Thaler

Bernard

Tod

et al. 1995

Antimicrob Agents Chemother

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We studied fluconazole penetration in the brain in five patients who had a deep cerebral tumor whose removal required the excision of healthy brain tissue. Plasma and brain samples were simultaneously obtained after oral ingestion of 400 mg of fluconazole daily for 4 days (90% of steady state). Fluconazole penetration in healthy cerebral parenchyma was determined. Plasma and brain samples were assayed by high-pressure liquid chromatography. Concentrations in plasma and brain tissue were 13.5 ؎ 5.5 g/ml and 17.6 ؎ 6.6 g/g, respectively. The average ratio of concentrations in the brain and plasma (four patients) was 1.33 (range, 0.70 to 2.39). Despite the lack of data concerning the penetration of fluconazole in brain abscesses, these results should permit the use of a daily dose of 400 mg of fluconazole in prospective clinical studies that evaluate the effectiveness of this drug in the treatment of brain abscesses due to susceptible species of fungi.Fluconazole, a triazole compound, is a systemic antifungal synthetic agent. Its fungistatic action is the inhibition of fungal cytochrome P-450 sterol C-14 alpha demethylation (18). During recent years, an increase in the rate of central nervous system fungal infections mainly due to an increased prevalence of immunosuppressed states (e.g., AIDS, malignancies, and organ transplantation) has been reported. Treatment by fluconazole of invasive infections due to various fungi has been a significant advance in antimicrobial chemotherapy (1,19,21). Its efficacy in treating cryptococcal and coccidioidal meningitis (2,3,5,14,22,23) is well established in clinical studies.In acute AIDS-associated cryptococcal meningitis fluconazole was shown to be as effective as amphotericin B (23) and more so in preventing relapse (3,22). However, use of fluconazole for treatment of this disease remains controversial (6,20,24), and the optimal dose remains uncertain. The incidence of cryptococcal intracerebral lesions is unknown and probably underestimated (6,8,11,27). Inadequate control of these lesions is perhaps one of the risk factors for failure or relapse of cryptococcal meningitis. Actually, therapeutic failures and relapses may occur when using amphotericin B or fluconazole (400 mg/day), and higher doses of fluconazole as salvage therapy have been proposed (2).While the penetration of fluconazole in human cerebrospinal fluid is known to be good (60 to 80% of levels in serum) (10, 25), data regarding its penetration in brain tissue other than in animals are lacking (17,26). The objective of this research was to study the penetration of fluconazole in human brain tissue and to determine the ratio of concentrations in the brain and plasma at steady state. MATERIALS AND METHODSObtaining brain tissue samples from patients with cryptococcal meningitis is not acceptable in light of current diagnostic and therapeutic strategies. Obtaining tissue samples from healthy volunteers is not conceivable. We therefore decided to study the penetration of fluconazole in the healthy cerebral parenchyma...

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A Controlled Trial of Fluconazole or Amphotericin B to Prevent Relapse of Cryptococcal Meningitis in Patients with the Acquired Immunodeficiency Syndrome

Abstract: Fluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B.

Cited by 331 publications

References 15 publications

Combination Antifungal Therapy

Combination Antifungal Therapy

Treatment of invasive fungal infections in cancer patients—Recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

Fluconazole penetration in cerebral parenchyma in humans at steady state

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