Ketoconazole Versus Nystatin Plus Amphotericin B for Fungal Prophylaxis in Severely Immunocompromised Patients

Hann, Ian; Corringham, Robert; Keaney, M.G.L.; Noone, Paul; Fox, J. T.; Szawatkowski, Melvyn; Prentice, H. G.; Blacklock, Hilary; Shannon, Michael; Gascoigne, E.; Boesen, Evelyn; Hoffbrand, A. V.

doi:10.1016/s0140-6736(82)91874-8

Cited by 139 publications

(26 citation statements)

References 16 publications

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“…Thus two different approaches have been proposed to study the problem of opportunistic fungal infections in cancer patients; on one hand, chemoprophylaxis with ketoconazole [12,18,19]-an oral systemic antifungal agent with few side effectsand on the other hand, in bacterial infections, early empirical therapy with amphotericin B in neutropenic patients with febrile episodes not responding to antibacterial agents [1,26].…”

Section: Discussionmentioning

confidence: 99%

“…Both patients in the ketoconazole group succumed to the infection in spite of therapy with amphotericin Band 5-flucytosine, whereas the two patients in the placebo group were cured. This observation might not be fortuitous because antagonism of amphotericin B by ketoconazole is as marked for C. albicans as it is for Aspergilli (A. S., unpublished observations) [15].A recent study from England [18] compared the efficacy of ketoconazole with oral amphotericin B and nystatin and suggested there was a reduction in the incidence of fungal infection in high-risk patients receiving ketoconazole. This study fails, however, to provide data that permit discrimination between superficial fungal infections, such as thrush, and disseminated opportunistic mycoses.…”

Section: Discussionmentioning

confidence: 99%

“…Because imidazoles have the potential to antagonize the antifungal activity of amphotericin B [13][14][15] (the most effective drug for therapy of most invasive opportunistic mycoses, including aspergillosis [16,17]), we became interested in the question of whether ketoconazole prophylaxis that was recently advocated in neutropenic patients [12,18,19] would influence the efficacy of a subsequent therapy of aspergillosis with amphotericin B. We therefore investigated the effects of ketoconazole on the susceptibility of aspergilli to amphotericin B in vitro and in vivo in neutropenic mice.…”

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confidence: 99%

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The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

Schaffner

1985

Journal of Infectious Diseases

178

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The potential of ketoconazole prophylaxis to antagonize the activity of amphotericin B against aspergilli was investigated in vitro and in neutropenic mice. Exposure of Aspergillus fumigatus (six strains) and of Aspergillus f/avus or Aspergillus niger to ketoconazole resulted in a uniform increase of the minimal fungicidal activity of amphotericin B, from 0.15-0.63 mg/liter to >2.5 mg/liter in a microwell assay. To test the relevance of this antagonism in vivo, we challenged neutropenic mice iv with a lethal dose of conidia from two strains of A. fumigatus and then treated the mice first with ketoconazole and then with amphotericin B or amphotericin B plus ketoconazole. Pretreatment with ketoconazole for 48 hr completely abolished the protective effect of a subsequent therapy with amphotericin B, whether ketoconazole therapy was stopped (P < . (01) or not (P < .001). Ketoconazole given alone had no significant effect on survival. Our data show that ketoconazole not only antagonized the fungicidal activity of amphotericin B in vitro but also abolished in vivo the protective effect of the only drug shown to be useful in the therapy of aspergillosis. The clinicalimportance of this antagonism, which is not limited to Aspergilli in vitro, requires careful consideration before ketoconazole prophylaxis can be recommended for patients at high risk of developing invasive opportunistic fungal infections.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

Schaffner

1985

Journal of Infectious Diseases

178

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“…Since then ketoconazole, fluconazole, clotrimazole, itraconazole, neomycin sulphate, colistin, trimethoprin and sulphamethoxazole have been tried in combination and at different concentrations for treatment of oral candidiasis (Hann, et al, 1982, Owens, et al, 1984, Palmblad, et al, 1992, Philpott-Howard, et al, 1993, Rozenberg-Arska, et al, 1991, Vogler, et al, 1987. Most recently ketoconazole and clotrimazole were found most effective in treatment of oral candidiasis (Worthington, et al, 2002).…”

Section: Treatmentmentioning

confidence: 99%

Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era

Krishna¹,

Zemse²,

DeRossi³

2011

Global View of HIV Infection

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“…Agents which have good oral bioavailability, a long half-life, high tissue penetration, minimal toxicity, and broad antifungal activity in immunocompromised patients are needed. Currently available drugs are either toxic and available only in intravenous form (amphotericin B) or are erratically absorbed and variably effective in immunocompromised patients (ketoconazole) (2).…”

mentioning

confidence: 99%

Pharmacokinetics and tissue penetration of Sch 39304 in granulocytopenic and nongranulocytopenic rabbits

Lee

Lin

Loebenberg

et al. 1989

Antimicrob Agents Chemother

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We studied the plasma pharmacokinetics and tissue penetration of Sch 39304 (SCH), a new antifungal triazole, in granulocytopenic [G(+)] and nongranulocytopenic [G(-)] rabbits. Five female New Zealand White G(-) rabbits were given a single oral dose of 2 mg of SCH per kg of body weight. Levels in plasma, determined by gas-liquid chromatography-electron capture, were obtained for 6 days. This procedure was repeated 2 weeks later with the same rabbits, which were induced and maintained G(+) with cytosine arabinoside. There were no significant differences between the pharmacokinetic parameters of G(+) and G(-) rabbits. Among all animals studied, the maximum concentration of the drug in plasma was 1.4 +/- 0.11 micrograms/ml at 4 +/- 0.5 h, the half-life was 25 +/- 1.4 h, the volume of distribution at steady state was 3.8 +/- 0.3 liters, and the area under the concentration-time curve was 44 +/- 3.4 micrograms.h/ml. SCH was detectable in plasma up to day 6. Levels of SCH in tissue were studied at steady state in six G(+) and six G(-) rabbits receiving 2 mg of the drug orally per kg per day for experimental disseminated candidiasis. Tissue SCH levels equalled or exceeded those in plasma (at steady state) at all sites examined, and these ratios were similar in both G(+) and G(-) rabbits. Thus, plasma pharmacokinetics of orally administered SCH were similar for G(+) and G(-) rabbits, and SCH achieved high levels of penetration into multiple tissues, including the liver and the central nervous system.

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Ketoconazole Versus Nystatin Plus Amphotericin B for Fungal Prophylaxis in Severely Immunocompromised Patients

Cited by 139 publications

References 16 publications

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

The Effect of Ketoconazole on Amphotericin B in a Model of Disseminated Aspergillosis

Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era

Pharmacokinetics and tissue penetration of Sch 39304 in granulocytopenic and nongranulocytopenic rabbits

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