Itraconazole Therapy for Cryptococcal Meningitis and Cryptococcosis

Denning, David W.; Tucker, Richard; Hanson, L H; Hamilton, John R.; Stevens, David A.

doi:10.1001/archinte.1989.00390100107024

Cited by 184 publications

(47 citation statements)

References 27 publications

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“…This effect has been documented for ketoconazole (17). A similar correlation between low levels in serum and unfavorable outcomes with itraconazole therapy was described by Denning et al (6). The unfavorable outcomes in these two patients may also have been influenced by the underlying immune dysfunction in these patients.…”

Section: Discussionsupporting

confidence: 74%

“…However, the arrest of progressive disease in patient 1 (phaeohyphomycosis) suggested that itraconazole is efficacious in some central nervous system infections. Additionally, favorable results in the treatment of cryptococcal meningitis in AIDS patients have been noted in other studies (6,39).…”

Section: Discussionmentioning

confidence: 63%

“…1, curve c). At 6 weeks, the patient experienced weakness, fatigue, orthostatic dizziness, intolerance of sun and heat, and edema prominent in the face and lower extremities. The cortisol response at that time (Fig.…”

Section: Methodsmentioning

confidence: 99%

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High-dose itraconazole in the treatment of severe mycoses

Sharkey

Rinaldi

Dunn

et al. 1991

Antimicrob Agents Chemother

139

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Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (<2.5 ,ug/ml) in both patients. All other patients had mean trough levels in serum above 5 ,ug/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 63%

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High-dose itraconazole in the treatment of severe mycoses

Sharkey

Rinaldi

Dunn

et al. 1991

Antimicrob Agents Chemother

139

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“…spergillus fumigatus is an opportunistic pathogen that causes life-threatening invasive disease in immunocompromised hosts (1). Its asexual spores, named conidia, are the initial source of inocula for infection and are the vehicles for dispersal and survival.…”

mentioning

confidence: 99%

Laccases Involved in 1,8-Dihydroxynaphthalene Melanin Biosynthesis in Aspergillus fumigatus Are Regulated by Developmental Factors and Copper Homeostasis

2013

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Aspergillus fumigatus produces heavily melanized infectious conidia. The conidial melanin is associated with fungal virulence and resistance to various environmental stresses. This 1,8-dihydroxynaphthalene (DHN) melanin is synthesized by enzymes encoded in a gene cluster in A. fumigatus, including two laccases, Abr1 and Abr2. Although this gene cluster is not conserved in all aspergilli, laccases are critical for melanization in all species examined. Here we show that the expression of A. fumigatus laccases Abr1/2 is upregulated upon hyphal competency and drastically increased during conidiation. The Abr1 protein is localized at the surface of stalks and conidiophores, but not in young hyphae, consistent with the gene expression pattern and its predicted role. The induction of Abr1/2 upon hyphal competency is controlled by BrlA, the master regulator of conidiophore development, and is responsive to the copper level in the medium. We identified a developmentally regulated putative copper transporter, CtpA, and found that CtpA is critical for conidial melanization under copper-limiting conditions. Accordingly, disruption of CtpA enhanced the induction of abr1 and abr2, a response similar to that induced by copper starvation. Furthermore, nonpigmented ctpA⌬ conidia elicited much stronger immune responses from the infected invertebrate host Galleria mellonella than the pigmented ctpA⌬ or wild-type conidia. Such enhancement in eliciting Galleria immune responses was independent of the ctpA⌬ conidial viability, as previously observed for the DHN melanin mutants. Taken together, our findings indicate that both copper homeostasis and developmental regulators control melanin biosynthesis, which affects conidial surface properties that shape the interaction between this pathogen and its host.A spergillus fumigatus is an opportunistic pathogen that causes life-threatening invasive disease in immunocompromised hosts (1). Its asexual spores, named conidia, are the initial source of inocula for infection and are the vehicles for dispersal and survival. Under favorable conditions, conidia break dormancy and grow as elongated, highly polarized hyaline hyphae. Upon achieving competency and exposure to air, hyphae produce aerial conidiophore stalks and develop elaborate multicellular conidiophores that generate chains of melanized uninucleate conidia (2, 3) (Fig. 1A and B). BrlA, a C 2 H 2 zinc finger transcription factor, is the master regulator that controls the initiation of conidiophore development in Aspergillus (4, 5). AbaA and WetA, two other important regulators that function downstream of BrlA, are required for proper progression of conidiation (6). The abaA gene is activated during the middle stage of conidiophore development, while the wetA gene is required for the activation of late conidiation-specific genes.The 1,8-dihydroxynaphthalene (DHN) melanin coating A. fumigatus conidia gives them their characteristic bluish green color (Fig. 1B). Melanin is an amorphous polymer that is produced by a variety of microbes and ...

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“…Itraconazole is an alternative, albeit less effective, choice for maintenance therapy. Oral itraconazole if patient is intolerant of fluconazole, may be administered (200 mg per day or a higher dosage 200 mg twice per day orally) (Denning et al, 1989).…”

Section: Cryptococcosis and Aidsmentioning

confidence: 99%