Invasive Infections Due to Candida krusei: Report of Ten Cases of Fungemia that Include Three Cases of Endophthalmitis

Candida krusei has become an increasingly important invasive pathogen, particularly in immunocompromised patients. Previous experimental and clinical experience suggest that C. krusei has a low propensity for hematogenously infecting the eye. We report 10 cases of fungemia due to C. krusei at our institutions, including three cases of endophthalmitis due to C. krusei. Fungemia was associated with nodular skin lesions in all seven patients with neutropenia and occurred despite administration of antifungal prophylaxis or empirical therapy. None of the patients apparently died as a direct result of C. krusei fungemia. Treatment with amphotericin B resulted in resolution of endophthalmitis, although one patient required vitrectomy. Early institution of aggressive therapy with amphotericin B may alter the course and improve the prognosis of C. krusei infection, particularly in immunocompromised patients. © 1992, by The University of Chicago.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Buprenorphine assay and plasma concentration monitoring in HIV-infected substance users

The availability of buprenorphine (BUP) provides an alternative approach to the treatment of opioid addiction with methadone, an agent that has many drug–drug interactions when combined with antiretroviral therapy (ART). However, due to limited long-term pharmacokinetic studies in HIV-infected patients, the clinical use of BUP, a CYP450-3A4 substrate, will require that studies be conducted to examine safety, tolerability and pharmacokinetics when these drugs are taken for chronic treatment. One clinical approach could include plasma concentration monitoring to avoid under- or overdosing BUP secondary to drug interactions with ART. The measurement of BUP and its active metabolite, norbuprenorphine (NBUP) facilitates the addition of BUP to ART in an attempt to avoid drug toxicity as described in a recent report by Bruce et al. Therefore, our objective was to validate a BUP assay and integrate its application into an ongoing antiretroviral (ARV) plasma concentration monitoring program. A chromatographic method for monitoring BUP and its active metabolite, NBUP was investigated. An assay was developed that would facilitate BUP and ARV measurement from a single 3 mL blood sample (0.75 mL plasma required) in conjunction with a previously validated multiple ARV HPLC method. The method measures BUP and NBUP over the range from 0.25 to 50 ng/mL with mass spectrometry detection. Inter- and intra-assay variation was ≤11%, across the concentration range. The method quantitates BUP and NBUP plasma concentrations within the range of expected values from current BUP dosing guidelines. Use of this combined BUP and ARV plasma concentration monitoring approach for a representative patient receiving BUP, atazanavir and efavirenz demonstrated its clinical application

Combination of anti-retroviral drugs and radioimmunotherapy specifically kills infected cells from HIV infected individuals

Eliminating virally infected cells is an essential component of any HIV eradication strategy. Radioimmunotherapy (RIT), a clinically established method for killing cells using radiolabeled antibodies, was recently applied to target HIV-1 gp41 antigen expressed on the surface of infect-ed cells. Since gp41 expression by infected cells is likely down-regulated in patients on an-tiretroviral therapy (ART), we evaluated the ability of RIT to kill ART-treated infected cells us-ing both in vitro models and lymphocytes isolated from HIV-infected subjects. Human peripheral blood mononuclear cells (PBMCs) were infected with HIV and cultured in the presence of two clinically relevant ART combinations. Scatchard analysis of the 2556 human monoclonal anti-body to HIV gp41 binding to the infected and ART-treated cells demonstrated sufficient residual expression of gp41 on the cell surface to warrant subsequent RIT. This is the first time the quantification of gp41 post-ART is being reported. Cells were then treated with Bismuth-213-labeled 2556 antibody. conjugated to the human monoclonal antibody 2556, which binds to HIV gp41. Cell survival was quantified by Trypan blue and residual viremia by p24 ELISA. Cell surface gp41 expression was assessed by Scatchard analysis. The experiments were repeated using PBMCs isolated from blood specimens obtained from 15 HIV-infected individuals: ten on ART and five ART-naive. We found that 213Bi-2556 killed ART-treated infected PBMCs and reduced viral production to undetectable levels. ART and RIT co-treatment was more effective at reducing viral load in vitro than either therapy alone, indicating that gp41 expression under ART was sufficient to allow 213Bi-2556 to deliver cytocidal doses of radiation to infected cells. This study provides proof of concept that 213Bi-2556 may represent an innovative and effective targeting method for killing HIV-infected cells treated with ART, and supports continued development of 213Bi-2556 for co-administration with ART towards an HIV eradication strategy

Lipid-Lowering Therapy in HIV-Infected Patients: Relationship with Antiretroviral Agents and Impact of Substance-Related Disorders

The use of combination antiretroviral therapy (cART) has significantly decreased the morbidity and mortality associated with human immunodeficiency virus (HIV) infection. Lipid disorders, including lipodystrophy, hypertriglyceridemia, and hypercholesterolemia, remain the most commonly reported metabolic disorders among those treated with long-term cART. Mounting evidence suggests an association between drug abuse and poor glycemic control and diabetes complications. Substance related disorders (SRD) may increase the risk of metabolic syndrome. The aim of this retrospective cohort study was to examine the relationship between SRD, cART, and lipid-lowering agent use in an HIV infected population. Patients received efavirenz or protease inhibitor-based cART for at least 6 months. Prescription information was retrieved from the medical records. The primary outcome was the use of lipid-lowering agents including statins, fibrates and fish oil. The impact of SRD and cART was assessed on the lipid-lowering agent use. A total of 276 subjects with HIV infection were included, 90 (33%) received lipid-lowering agents, and 31 (34%) had SRD. Smoking was prevalent among subjects with SRD (84 vs 15%, p<0.001). Statins were the mainstay for the management of dyslipidemia (66%), followed by the fibrates (24%), omega-3 fatty acids (5%), nicotinic acid (3%) and the cholesterol absorption inhibitors (3%). Use of statins or fibrates was significantly higher among subjects without SRD than those with (40 vs 23%, p=0.005). The type of cART, including efavirenz and protease inhibitors, appeared to have no significant impact on the use pattern of lipid-lowering agents. Lopinavir/ritonavir (lopinavir/r) was mostly prescribed for subjects with SRD (25 vs 8%, p=0.02). Among HIV-infected patients, statins remain the mainstay for the management of dyslipidemia in routine clinical care, followed by fibrates. A significant high risk of metabolic disorders among patients with SRD is implicated by heavy tobacco use and prevalent lopinavir/r-based treatment. Significantly low rate of lipid-lowering agent use in this population underscores the importance of lipid disorder scrutiny and cART treatment optimization for HIV-infected patients with SRD

Multidrug resistance 1 polymorphisms and trough concentrations of atazanavir and lopinavir in patients with HIV

HIV-infected patients receiving protease inhibitors may benefit from therapeutic drug monitoring-assisted dose adjustment to achieve target plasma concentrations. However, efflux pumps such as permeability-glycoprotein, which is encoded by the multidrug resistance ( ) gene, may decrease intracellular drug concentrations, thus reducing the amount of drug at the site of action. Plasma concentrations of protease inhibitors and CD4 cell count response have been associated with the T allele at the C3435T locus. We examined single nucleotide polymorphisms in a cohort of patients in whom therapeutic drug monitoring is ongoing through a research protocol. In a multicenter study, genotypic analyses at two loci, C3435T and G2677T, were performed by a real-time polymerase chain reaction method using DNA from 103 patients categorized as substance users or nonusers on atazanavir or lopinavir as the primary antiretrovirals. Allelic frequencies were determined as a function of racial/ethnic background, substance use status and trough concentrations of atazanavir and lopinavir. The C/T and G/T alleles at the C3435T and G2677T loci were equally frequent in the Caucasian population, but the wild-type alleles were more prevalent in the African-American population (59% homozygous [CC] and 32% heterozygous [CT] for C3435T; 80% homozygous [GG] and 16% heterozygous [GT] for G2677T). The frequencies in the Hispanic population were 46% CC and 38% CT for C3435T, and 58% GG and 38% GT for G2677T. No significant differences were seen in allele frequencies for polymorphisms in substance user versus nonuser groups. Trough plasma concentrations of atazanavir or lopinavir were not correlated with the variant T allele. These data confirm the higher prevalence of wild-type alleles of the gene in African-Americans and the linkage disequilibrium between C3435T and G2677T loci. The T allele at the C3435T and G2677T loci was not associated with higher atazanavir or lopinavir trough concentrations