Huander Felipe Andreolla

Voriconazole therapeutic drug monitoring: focus on safety

Importance of the field: Voriconazole has been widely used for the treatment of invasive fungal diseases, particularly invasive aspergillosis. Drug–drug interactions are, however, the main drawback associated with voriconazole use, since this drug suffers from extensive hepatic metabolism. Areas covered in this review: This article reviews the current literature on voriconazole therapeutic drug monitoring, with a special focus on drug safety. What the reader will gain: An update on voriconazole metabolism, drug interactions, toxicity and the relation of these with voriconazole drug concentrations. Take home message: Therapy with voriconazole may be better guided by measuring voriconazole concentrations in the plasma.

Endoxifen levels and its association with CYP2D6 genotype and phenotype: evaluation of a southern Brazilian population under tamoxifen pharmacotherapy.

Background: An association between CYP2D6 variation and clinical outcomes among women with breast cancer treated with tamoxifen (TAM) has been demonstrated, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes. This association is mainly due to the CYP2D6-mediated hydroxylation of N-desmethyltamoxifen (NDT) to yield endoxifen (EDF), which because of its high antiestrogenic potency, is mainly responsible for the therapeutic efficacy of TAM. The aim of this study was to evaluate the relation of CYP2D6 genotyping and phenotyping with EDF levels and [NDT]/[EDF] metabolic ratio in breast cancer patients from South of Brazil under TAM therapy. Methods: Trough blood samples were collected from 97 patients. CYP2D6 genotyping was performed with a luminex assay and calculation of genotypic activity scores. Tamoxifen and metabolites EDF, NDT, and 4-hydroxy-TAM were measured in plasma by high performance liquid chromatography with photo diode array detector. CYP2D6 phenotyping was performed by the determination of dextromethorphan (DMT) and dextrorphan (DTF) by high-performance liquid chromatography with fluorescence detection at plasma collected 3 hours after oral administration of 33 mg of DMF. Phenotypes were given according to [DMT]/[DTF] metabolic ratio. Results: CYP2D6 genotyping indicated a prevalence of 4.1% poor metabolizer, 4.1% intermediate metabolizer, 49.5% extensive metabolizer slow activity, 39.2% extensive metabolizer fast activity, and 3.1% ultrarapid metabolizer. Genotype (genotypic activity scores) was significantly correlated with phenotype ([DMT]/[DTF]), with a moderate association (rs = −0.463; P < 0.001). Median plasma concentrations (nanograms per milliliter; N = 97) were TAM 57.17; 4-hydroxy-TAM 1.01; EDF 6.21; NDT 125.50. EDF levels were lower in poor metabolizers than that in extensive metabolizers (P < 0.05). Phenotype showed stronger, but still moderate, association with EDF and [NDT]/[EDF] than genotype (r = −0.507, r = 0.625, P < 0.001 versus r = 0.356, r = 0.516, P < 0.01). Phenotype accounted for 26% of the variability in EDF levels and 38% of [NDT]/[EDF], whereas genotype accounted for 12% and 27%, respectively. Conclusions: CYP2D6 genotyping and/or phenotyping could not fully predict EDF concentrations. Monitoring EDF itself could be considered during TAM therapy.

The performance of real-time PCR, galactomannan, and fungal culture in the diagnosis of invasive aspergillosis in ventilated patients with chronic obstructive pulmonary disease (COPD).

Emerging reports have associated chronic pulmonary obstructive disease (COPD) with invasive aspergillosis (IA), particularly in patients treated with mechanical ventilation and/or corticosteroids. This is a multicentre study in which COPD patients demonstrating a new lung infiltrate while being mechanically ventilated were prospectively evaluated for the presence of IA. From the 47 patients studied, Aspergillus fumigatus was recovered in culture in two patients (4.2%). While serum galactomannan (GM) was negative for 94% of patients, GM levels in respiratory samples were >0.5, >1.0 and >1.5 for 74.5, 40.5, and 21.3% of patients, respectively. PCR was positive for 10 patients in the study but did not differentiate Aspergillus colonization from infection. The combination of PCR and GM in respiratory samples may be an interesting alternative to diagnose IA in COPD patients.

Clinical, laboratorial and radiographic predictors of Bordetella pertussis infection

OBJECTIVE: To identify clinical, laboratorial and radiographic predictors for Bordetella pertussis infection. METHODS: This was a retrospective study, which analyzed medical records of all patients submitted to a molecular dignosis (qPCR) for B. pertussis from September 2011 to January 2013. Clinical and laboratorial data were reviewed, including information about age, sex, signs/symptoms, length of hospitalization, blood cell counts, imaging findings, coinfection with other respiratory pathogens and clinical outcome. RESULTS: 222 cases were revised. Of these, 72.5% had proven pertussis, and 60.9% were under 1 year old. In patients aging up to six months, independent predictors for B. pertussis infection were (OR 8.0, CI 95% 1.8-36.3; p=0.007) and lymphocyte count >104/µL (OR 10.0, CI 95% 1.8-54.5; p=0.008). No independent predictors of B. pertussis infection could be determined for patients older than six months. Co-infection was found in 21.4% of patients, of which 72.7% were up to six months of age. Adenovirus was the most common agent (40.9%). In these patients, we were not able to identify any clinical features to detect patients presenting with a respiratory co-infection, even though longer hospital stay was observed in patients with co-infections (12 vs. 6 days; p=0.009). CONCLUSIONS: Cyanosis and lymphocytosis are independent predictors for pertussis in children up to 6 months old.

Lack of association between helicobacter pylori's virulence and increased serum C-reactive protein levels in functional dyspeptic patients

BACKGROUND Recently, a great variety of studies aimed to investigate and even suggest Helicobacter pylori as an important key factor in gastrointestinal and non-gastrointestinal events development. The well-established relationship between bacterial virulence and increased risk for peptic ulcer or gastric carcinoma is not so clear when comparing inflammation markers alterations, such C-reactive protein, with the pathogen. OBJECTIVE The objective of this study was to evaluate the presence of H. pylori, bacterial virulence and C-reactive protein serum levels in individuals diagnosed with functional dyspepsia. METHODS Were prospectively included in this study 489 dyspeptic individuals. They fulfill Rome III clinical criteria for the diagnosis of functional dyspepsia with no organic disease at endoscopy. The bacterial infection was established by histology and urease rapid test. The levels of serum C-reactive protein were obtained by immunonefelometry and CagA status of H. pylori positive individuals was determined through an imunoenzimatic assay. RESULTS Prevalence rate of H. pylori was 66.3% and virulence factor CagA was detected in nearly 43% of positive samples. In addition, it has been noticed an association between Ilex paraguariensis (yerba maté) consumption and pathogens prevalence. An important effect of bacterial infection on inflammation was only observed in gastric epithelium. CONCLUSION No systemic response to the pathogen, measured through C-reactive protein levels, was observed, regardless of CagA status. Otherwise, the intake of yerba maté should be considered as a cultural factor possibly related to H. pyloris transmission.

Ultra-performance liquid chromatographic method for measurement of voriconazole in human plasma and oral fluid

A simple, sensitive and selective ultra-performance liquid chromatography method for the determination of voriconazole in plasma and oral fluid was developed and validated. After a liquid-liquid extraction with methyl-tert-butyl ether, the analyte and internal standard were separated on a Hypersil Gold C18 column (2.1 × 100 mm, p.d. 1.9 µm), eluted with a mobile phase composed of thietylammonium phosphate buffer and acetonitrile (70:30, v/v). Total run time was 4 min, total mobile phase consumption of 2.2 mL. Detection was performed with a photodiode array detector with quantitation at 256 nm. Voriconazole concentrations in oral fluid were on average 57.5% (±5.3) of those measured in paired plasma samples.