Voriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype.

BACKGROUND: Prospective evaluation of the antifungal drug, voriconazole, is needed to determine whether drug toxicity correlates with CYP2C19 genotype or serum concentrations of voriconazole or its metabolites. METHODS: We conducted a prospective study of 95 patients to determine voriconazole toxicity and its relationship to genotype and serum levels of voriconazole and its two metabolites. Efficacy was not evaluated because, in most cases, the drug was given for empirical or prophylactic therapy. RESULTS: Hallucinations occurred in 16 patients (16.8%), visual changes in 17 (17.9%), photosensitivity in 10 (10.5%), and hepatotoxicity in 6 (6.3%). There was no correlation between photosensitivity or hepatotoxicity and levels of voriconazole or metabolites. Patients with hallucinations had higher average voriconazole levels (4.5 vs 2.5 µg/mL) but with extensive overlap. The recommended oral dose of 200 mg did not provide consistently detectable serum voriconazole levels in adults. CYP2C19 and CYP2C9 genotypes had a minor influence over levels, though the 4 patients homozygous for the 2C19*2 genotype had higher average levels for voriconazole (4.3 vs 2.5 µg/mL) and lower N-oxide levels (1.6 vs 2.5 µg/mL). CONCLUSIONS: CYP2C19 and 2C9 genotypes were not major determinants of voriconazole metabolism. No toxic serum level of voriconazole or its metabolites could be identified.

Idiopathic CD4 lymphocytopenia: a case of missing, wandering or ineffective T cells.

Idiopathic CD4 lymphocytopenia (ICL) is a presumed heterogenous syndrome with key element low CD4 T-cell counts (below 300/mm³) without evidence of HIV infection or other known immunodeficiency. The etiology, pathogenesis, and management of ICL remain poorly understood and inadequately defined. The clinical presentation can range from serious opportunistic infections to incidentally diagnosed asymptomatic individuals. Cryptococcal and non-tuberculous mycobacterial infections and progressive multifocal leukoencephalopathy are the most significant presenting infections, although the spectrum of opportunistic diseases can be similar to that in patients with lymphopenia and HIV infection. Malignancy is common and related to opportunistic pathogens with an oncogenic potential. Autoimmune diseases are also seen in ICL with an increased incidence. The etiology of ICL is unknown. Mechanisms implicated in CD4 reduction may include decreased production, increased destruction, and tissue sequestration. New distinct genetic defects have been identified in certain patients with ICL, supporting the hypothesis of the lack of a common etiology in this syndrome. The management of ICL is focused on the treatment of opportunistic infections, appropriate prophylactic antibiotics, and close monitoring. In selected patients with life-threatening infections or profound immunodeficiency, strategies to increase T-cell counts or enhance immune function could be considered and have included interleukin-2, interferon-gamma, interleukin-7, and hematopoietic stem cell transplantation. The prognosis is influenced by the accompanying opportunistic infections and may be affected by publication bias of severe cases with unfavorable outcomes. As newer laboratory investigation techniques are being developed and targeted experimental treatments become available, our comprehension and prognosis of this rare syndrome could be significantly improved.

Hallucinations during voriconazole therapy.

As part of a prospective natural history cohort study of voriconazole toxicity, we describe the characteristics of 12 of 72 voriconazole-treated patients who experienced hallucinations from March 2006 through November 2007. Hallucinations associated with voriconazole use are not uncommon. Doctors should be aware of this complication, and the recipients of the drug should be reassured that the hallucinations are an effect of the drug.

Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors.

Idiopathic CD4(+) lymphocytopenia (ICL) is a rare non-HIV-related syndrome with unclear natural history and prognosis. This prospective natural history cohort study describes the clinical course, CD4 T lymphocyte kinetics, outcome, and prognostic factors of ICL. Thirty-nine patients (17 men, 22 women) 25 to 85 years old with ICL were evaluated between 1992 and 2006, and 36 were followed for a median of 49.5 months. Cryptococcal and nontuberculous mycobacterial infections were the major presenting opportunistic infections. Seven patients presented with no infection. In 32, CD4 T-cell counts remained less than 300/mm(3) throughout the study period and in 7 normalized after an average of 31 months. Overall, 15 (41.6%) developed an opportunistic infection in follow-up, 5 (13.8%) of which were "AIDS-defining clinical conditions," and 4 (11.1%) developed autoimmune diseases. Seven patients died, 4 from ICL-related opportunistic infections, within 42 months after diagnosis. Immunologic analyses revealed increased activation and turnover in CD4 but not CD8 T lymphocytes. CD8 T lymphocytopenia (< 180/mm(3)) and the degree of CD4 T cell activation (measured by HLA-DR expression) at presentation were associated with adverse outcome (opportunistic infection-related death; P = .003 and .02, respectively).

Update on azole antifungals.

This is a comprehensive, clinically oriented review of the four commercially available triazoles: fluconazole, itraconazole, voriconazole, and posaconazole. Emphasis is placed in pharmacology, drug interactions, adverse events, antifungal activity, and the evolving perspective of their clinical use. Key clinical trials are briefly discussed, and specific drug indications summarized. Fluconazole remains a valuable low-cost choice for the treatment of various fungal infections, including candidiasis and cryptococcosis. It has relatively few drug interactions and is safe but lacks activity against filamentous fungi. The use of itraconazole is historically plagued by erratic bioavailability of the oral capsule, improved with the oral solution. Drug interactions are numerous. Itraconazole exhibits significant activity against Aspergillus and the endemic fungi. Voriconazole has revolutionized the treatment of aspergillosis in severely immunocompromised patients, but its use is compromised by complicated pharmacokinetics, notable drug interactions, and relatively significant adverse events. Finally, posaconazole is the last addition to the azole armamentarium with extended antifungal spectrum, significant activity against the zygomycetes, and, apparently, optimal safety profile. Posaconazole has a significant role for the prophylaxis of invasive fungal infections in severely immunocompromised patients. Multiple daily dosing, a need for fatty foods for absorption, and absence of an intravenous formulation restrict its use to selected populations.

Cryptococcosis and idiopathic CD4 lymphocytopenia.

We reviewed the cases of 11 patients with cryptococcosis and idiopathic CD4 lymphocytopenia (ICL) referred to our institution in the previous 12 years, as well as 42 similar cases reported in the literature, to assess the characteristics of the infection in this population. Cryptococcosis in 53 patients with ICL had features in common with cryptococcosis in previously normal patients. ICL patients had a slight male predominance (1.2:1) and a median age of presentation of 41 years (range, 4.5-85 yr). Initial cerebrospinal fluid findings showed glucose below 40 mg/dL in 60% of the patients, a median pleocytosis of 59 white blood cells/mm (range, 0-884), and protein of 156 mg/dL (range, 25-402 mg/dL). The median CD4 count at diagnosis of ICL and at the last available measurement was 82 (range, 7-292) and 132 (range, 13-892) cells/mm, respectively, for an average follow-up of 32 months in 46 patients. Unlike previously normal patients with cryptococcosis, those with ICL had an excess incidence of dermatomal zoster (7 episodes in 46 ICL cases). Pneumocystis pneumonia was rare (1 case), casting doubt on the need for prophylaxis in patients with ICL. A favorable outcome (cured or improved) may be more common in ICL patients than in previously normal patients with cryptococcal meningitis and no predisposing factors. Identification of ICL in patients who were apparently normal before the onset of cryptococcosis appears to be useful because it predicts a favorable outcome. Patients with cryptococcal infection and ICL have an increased likelihood of developing dermatomal zoster. The long-term follow-up of these patients offers some reassurance regarding favorable prognosis.

Campylobacter fetus bacteraemia in a healthy individual: clinical and therapeutical implications.

Campylobacter species are well-recognized common causes of gastrointestinal infections. While Campylobacter jejuni is probably the most common Campylobacter isolated in humans, Campylobacter fetus is rather infrequent and mostly related with bacteraemia. Even on such occasions, it seems that immunocompetent individuals are spared. We report a case of C. fetus bacteraemia in a healthy-except for impaired fasting glucose (IFG) levels-farmer, presenting as an acute febrile syndrome and treated successfully as brucellosis.

Gross chylous ascites in cirrhosis with massive portal vein thrombosis: diagnostic value of lymphoscintigraphy. A case report and review of the literature.

Chylous ascites is an uncommon condition, which could be due to various causes. We report a case of gross chylous ascites in a patient with cirrhosis and portal vein thrombosis. It is confirmed that gross chylous ascites in a patient with cirrhosis and portal vein thrombosis heralds an ominous prognosis for the patient. Results also demonstrate that common therapeutic interventions confer minimal benefit to the patient, whose survival may be limited to a few months. The use of lymphoscintigraphy as a convenient method for diagnostic exploration of the chylous ascites is emphasized, as it does not lead to complications or adverse effects, and can be readily repeated as needed.