RESUMO
Diagnosis and management of infectious diseases (ID) at the emergency department (ED) are challenging due to the peculiar setting and the available diagnostic tools. The involvement of an ID consultant has been described to improve clinical outcomes and antimicrobial stewardship (AMS) programs. An online survey was sent to 100 Italian Departments of Infectious Diseases affiliated with the Italian Society of Infectious Diseases and Tropical Medicine (SIMIT). The primary objective of our study was to describe the characteristics of ID services in Italian EDs to identify possible challenges and shortcomings and provide tips to improve the management of patients. Secondary objectives included the evaluation of diagnostic capability and the management of patients with suspected or confirmed ID. Seventy-six out of the 100 SIMIT centers, 32 (42.1%) of which were teaching hospitals, answered the survey. In 62 (82.7%) centers, consultations were performed by the IDs specialist on call. In 29 (38.2%) centers, there was a formal AMS program, and 32 (42.7%) had protocols for antibiotic use in the ED. Microbiological tests to be performed before starting antibiotic treatment in the ED were clearly defined in 44 (57.9%) hospitals. This survey highlighted several challenges in the current organization of ID consultations in Italian EDs.
Assuntos
Doenças Transmissíveis , Humanos , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/epidemiologia , Serviço Hospitalar de Emergência , Antibacterianos/uso terapêutico , Encaminhamento e Consulta , Itália/epidemiologia , Hospitais de EnsinoRESUMO
BACKGROUND: Treatment of patients with chronic hepatitis C who failed the triple therapy with first generation of protease inhibitors is not still defined. The combined use of sofosbuvir (SOF) and daclatasvir (DCV) seems to be promising due to higher genetic barrier, good tolerance and effectiveness. METHODS: We described the treatment with this drug combination in a real-life cohort of 20 cirrhotic patients with genotype 1 who failed the triple therapy. RESULTS: 18 of them (90%) with Child-Pugh A, 11 (55%) with genotype 1a, 17 (85%) with more than 1 and 8 (40%) with more than 2 previous failed treatment; all patients had at baseline NS3 resistance-associated variants related to triple therapy failure. RBV was not administered due to anemia in previous treatments. The sustained virological response was 100%. CONCLUSION: Treatment with SOF + DCV without RBV for 24 weeks is safe and effective in cirrhotic patients who failed triple therapy with the first generation of protease inhibitors.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Cirrose Hepática/complicações , Sofosbuvir/uso terapêutico , Carbamatos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/uso terapêutico , Pirrolidinas , Valina/análogos & derivadosRESUMO
Mixed cryoglobulinemia (MC) is the most frequent extrahepatic hepatitis C virus (HCV) complication. Vitamin D is a modulator of several biological processes, including immune and skeletal systems and MC presence and systemic vasculitis were associated independently with low levels of vitamin D. Considering the impact of vitamin D, we aimed to evaluate the role of some single nucleotide polymorphisms (SNPs) of vitamin D pathway genes in the prediction of MC in HCV patients treated with pegylated interferon and ribavirin. We investigated SNPs in IL-28B, CYP27B1, CYP27A1, CYP24A1, VDBP, and VDR genes through real-time PCR. VDR gene SNPs were related to baseline viral load: VDR BsmI AA (P=0.018), TaqI CC (P=0.009), and ApaI AA (P=0.004) showed a lower baseline HCV count. Among vitamin D pathway gene polymorphisms, VDR FokI T>C was a factor associated with the presence of MC in the study population (P=0.011): related to C allele carriers (TT vs. TC/CC), we obtained a P-value of 0.003. In the logistic regression analysis to assess which demographic, clinical, or genetic factors could predict the presence of cryoglobulin, the TT/CC IL-28B rs8099917/rs12979860 haplotype [P<0.001; odds ratio (OR) 3.516 (1.951-6.336)], baseline viral load [P<0.001; OR 1.000 (0.999-1.001)], and VDR FokI TC/CC genotypes [0.044; OR 0.463 (0.218-0.981)] remained in the final regression model. These data could help physicians identify patients with a higher probability of developing MC extrahepatic complications.
Assuntos
Crioglobulinemia/diagnóstico , Hepatite C Crônica/complicações , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Vitamina D/metabolismo , Adulto , Antivirais/uso terapêutico , Crioglobulinemia/etiologia , Feminino , Genótipo , Haplótipos/genética , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transdução de Sinais , Carga ViralRESUMO
OBJECTIVES: Infections caused by Klebsiella pneumoniae (Kp) carbapenemase (KPC)-producing strains of Kp have become a significant threat in recent years. To assess their outcomes and identify risk factors for 14 day mortality, we conducted a 4 year (2010-13) retrospective cohort study in five large Italian teaching hospitals. METHODS: The cohort included 661 adults with bloodstream infections (BSIs; nâ=â447) or non-bacteraemic infections (lower respiratory tract, intra-abdominal structure, urinary tract or other sites) caused by a KPC-Kp isolate. All had received ≥48 h of therapy (empirical and/or non-empirical) with at least one drug to which the isolate was susceptible. RESULTS: Most deaths occurred within 2 weeks of infection onset (14 day mortality: 225/661, 34.1%). Logistic regression analysis identified BSI (OR, 2.09; 95% CI, 1.34-3.29), presentation with septic shock (OR, 2.45; 95% CI, 1.47-4.08), inadequate empirical antimicrobial therapy (OR, 1.48; 95% CI, 1.01-2.18), chronic renal failure (OR, 2.27; 95% CI, 1.44-3.58), high APACHE III score (OR, 1.05; 95% CI, 1.04-1.07) and colistin-resistant isolates (OR, 2.18; 95% CI, 1.37-3.46) as independent predictors of 14 day mortality. Combination therapy with at least two drugs displaying in vitro activity against the isolate was associated with lower mortality (OR, 0.52; 95% CI, 0.35-0.77), in particular in patients with BSIs, lung infections or high APACHE III scores and/or septic shock at infection onset. Combinations that included meropenem were associated with significantly higher survival rates when the KPC-Kp isolate had a meropenem MIC of ≤8 mg/L. CONCLUSIONS: KPC-Kp infections are associated with high mortality. Treatment with two or more drugs displaying activity against the isolate improves survival, mainly in patients who are critically ill.
Assuntos
Antibacterianos/uso terapêutico , Proteínas de Bactérias/metabolismo , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/mortalidade , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/enzimologia , beta-Lactamases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Feminino , Hospitais de Ensino , Humanos , Itália/epidemiologia , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/isolamento & purificação , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
The role of measurement of hepatitis B "s" antigen (HBsAg) during the therapy with oral nucleos(t)ide analogues is still debatable. The HBsAg declines after 3 years of therapy with entecavir (ETV) was investigated among patients affected by hepatitis B virus (HBV), e antigen (HBeAg)-negative and genotypes A, D and E. A prospective cohort of 123 patients was enrolled consecutively from April 2007 to May 2010 with at least 3 years of treatment with ETV. Patients with chronic HBV infection, HBeAg-negative, naive for previous treatment and with virological response to ETV were included in the study. HBsAg level and HBV-DNA were tested every 3 months during the first year of treatment, then every 6 months for a time of at least 3 years. After 3 years, HBsAg decline was 0.77 log IU/ml, 0.65 log IU/ml, 0.45 respectively; A versus D (P = 0.012), A versus E (P < 0.001), D versus E (P < 0.001). In the multivariate linear regression analysis only the HBV genotype was predictive of HBsAg decline after 3 years of treatment (P < 0.001). The expected time to HBsAg loss was 15.6 years for the A genotype, 17 years for D, 24.6 years for E (P < 0.001). The treatment with ETV leads the different kinetics in HBsAg decline among genotypes A, D and E; the expected time of HBsAg loss was significantly higher in E genotype compared to A and D genotype.
Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , DNA Viral/sangue , Genótipo , Guanina/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
During the current SARS-CoV-2 pandemic, a novel syndrome termed "multisystem inflammatory syndrome in children" (MIS-C) has emerged. MIS-C was linked to COVID-19 and shared some features with Kawasaki disease and Toxic Shock Syndrome, with a common pathogenetic substrate of hyperinflammation and cytokine storm. Lately, MIS was also described in adults (≥21 years of age) and named "MIS-A". There is no consensus about the treatment of MIS-A; successful use of glucocorticoids and immunoglobulins has been reported in case series, but more solid evidence is lacking. Furthermore, the role of biologic agents with proven benefits against COVID-19, MIS-C, or Kawasaki disease is still unexplored. In this report, we detail the clinical picture and the diagnostic process that led to the diagnosis of MIS-A in a 27-year-old man, focusing on its treatment with anakinra and glucocorticoids, which resulted in full recovery. To our knowledge, this is the first report of the successful use of anakinra for MIS-A, a drug that has already proven useful in the treatment of refractive cases of MIS-C. Anakinra may also play a pivotal role for the treatment of MIS-A.
RESUMO
A high burden of epilepsy is observed in Africa where parasitological infections are endemic. In 2016, in an Onchocerciasis endemic area in the Logo health zone, in Ituri province in the Democratic Republic of Congo, a door-to-door study showed an epilepsy prevalence of 4.6%, and 50.6% of persons with epilepsy were infected with Onchocerca volvulus. In the current study, the serum of 195 people infected with O. volvulus persons with epilepsy were tested to determine the proportion of co-infections with Taenia solium, Toxocara canis and Strongyloides. These proportions were, respectively, 8.2, 18.5 and 12.8%. Persons with a T. solium co-infection were older than those without co-infection (p = 0.021). In six (37.5%) of the T. solium co-infected persons, the first seizures appeared after the age of 30 years compared to three (2.1%) persons without a co-infection (p < 0.0001). Our study suggests that an O. volvulus infection is the main parasitic cause of epilepsy in the Ituri province, but in some persons, mainly in those with late onset epilepsy and with focal seizures, the epilepsy may be caused by neurocysticercosis. As the population in the area rears pigs, activities to limit T. solium transmission should be implemented.
RESUMO
OBJECTIVES: To assess the antibody response to BNT162b2 mRNA COVID-19 vaccine in a cohort of health-care workers (HCW), comparing individuals with previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and SARS-CoV-2-naive individuals. METHODS: HCW were tested at T0 (day of first dose), T1 (day of second dose) and T2 (2-3 weeks after second dose) for IgG anti-nucleocapsid protein, IgM anti-spike protein and IgG anti-receptor binding domain (IgG-RBD-S). The antibody response was compared between four main groups: group A, individuals with previous infection and positive antibodies at baseline; group B, individuals with the same history but negative antibodies; group C, individuals with no infection history but positive antibodies; group D, naive individuals. Repeated measures analysis was used to compare results over time-points. RESULTS: A total of 1935 HCW were included. Median IgG-RBD-S titre was significantly higher for group A (232 individuals) than for group B (56 individuals) both at T1 (A: 22 763 AU/mL, interquartile range (IQR) 14 222-37 204 AU/mL; B: 1373 AU/mL, IQR 783-3078 AU/mL, p 0.0003) and T2 (A: 30 765 AU/mL, IQR 19 841-42 813 AU/mL; B: 13 171 AU/mL, IQR 2324-22 688 AU/mL, p 0.0038) and for group D (1563 individuals; 796 AU/mL, IQR 379-1510 AU/mL at T1; 15 494 AU/mL, IQR 9122-23 916 AU/mL at T2, p < 0.0001 for both time-points). T1 values of group A were also significantly higher than T2 values of group D (p < 0.0001). Presence of symptoms, younger age and being female were associated with stronger antibody response. HCW infected in March showed a significantly stronger response (T1: 35 324 AU/mL, IQR 22 003-44 531 AU/mL; T2: 37 648 AU/mL, IQR 27 088-50 451 AU/mL) than those infected in November (T1: 18 499 AU/mL, IQR 11 492-27 283 AU/mL; T2: 23 210 AU/mL, IQR 18 074-36 086 AU/mL, p < 0.0001 for both time-points. CONCLUSIONS: Individuals with past SARS-CoV-2 infection had a strong antibody response after one single vaccine shot. A single dose might be sufficient for this group, regardless of the time elapsed since infection; however, the clinical correlation with antibody response needs to be studied.
Assuntos
Anticorpos Antivirais/sangue , Formação de Anticorpos , Vacina BNT162/imunologia , COVID-19 , COVID-19/prevenção & controle , Pessoal de Saúde , Humanos , Imunoglobulina G/sangue , Estudos Prospectivos , RNA MensageiroRESUMO
Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/ß inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.
Assuntos
Tratamento Farmacológico da COVID-19 , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Idoso , COVID-19/virologia , Método Duplo-Cego , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos , SARS-CoV-2/isolamento & purificaçãoAssuntos
Bacteriemia/epidemiologia , Proteínas de Bactérias/metabolismo , Infecção Hospitalar/epidemiologia , Infecções por Klebsiella/epidemiologia , Klebsiella pneumoniae/isolamento & purificação , beta-Lactamases/metabolismo , Adulto , Idoso , Bacteriemia/microbiologia , Bacteriemia/mortalidade , Infecção Hospitalar/microbiologia , Infecção Hospitalar/mortalidade , Feminino , Instalações de Saúde , Humanos , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/mortalidade , Klebsiella pneumoniae/enzimologia , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
We measured ceftriaxone pharmacokinetics in patients' plasma and cerebrospinal fluid (CSF) and assessed the influence of biometric, demographic, genetic (ABCB1, ABCC2, ABCB11, ABCG2, and SLCO1A2 polymorphisms) and pathological features. Adult patients with signs and symptoms of central nervous system infections, receiving intravenous ceftriaxone, were enrolled. Ceftriaxone plasma and CSF concentrations were measured by high-precision liquid chromatographic methods; allelic discrimination was performed by real-time polymerase chain reaction. Forty-three patients were included: median ceftriaxone maximal concentration was 15,713 ng/mL in plasma and 3512 ng/mL in CSF with a CSF-to-plasma ratio of 0.3. ABCC2 1249 rs2273697 (P = .027) and ABCG2 1194+928 rs13120400 (P = .015) variants were significantly associated with CSF concentrations and CSF-to-plasma ratios. At linear regression analysis, CSF-to-serum albumin ratio was an independent predictor of ceftriaxone CSF concentrations (P = .001; also in those with intact blood-brain barrier: P = .031) and CSF-to-plasma ratio (P = .001; also in those with blood-brain barrier impairment: P = .040). We here report the role of transporters' genetic variants as well as of blood-brain barrier permeability in predicting ceftriaxone exposure in the central nervous system.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Ceftriaxona/sangue , Ceftriaxona/líquido cefalorraquidiano , Meningites Bacterianas/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Antibacterianos/sangue , Antibacterianos/líquido cefalorraquidiano , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Ceftriaxona/farmacocinética , Ceftriaxona/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência MúltiplaRESUMO
The new direct-acting antivirals agents (DAAs) rapidly changed the treatment approach in chronic hepatitis C (CHC); however, the interferon (IFN)-free therapies availability is currently different in some countries, due to higher costs of these drugs. Naïve treated patients, who are not eligible for IFN-free therapies, could be selected for standard dual treatment with pegylated (PEG)-IFN and ribavirin (RBV), through IFN lambda 3 gene polymorphisms and fibrosis stage evaluation. Inclusion criteria were: naïve treated CHC patients with GT1 or GT4, without major contraindication to PEG-IFN or RBV, with fibrosis stage F0-F2 and IFNL3 rs8099917/rs12979860 TT/CC genotypes. 65 patients were included in the study. Overall SVR was observed in 50 patients (76.9%); SVR rates among different genotypes were as follows: 15 with GT1a (71.4%), 27 with GT1b (79.4%) and 8 for GT4 (80%). The RBV cutoff at 2weeks of 1800ng/mL, predictor of RVR, was determined (p=0.003; sensibility=60.4%, specificity=88.2%, positive predictive value=88.9%, negative predictive value=100%). In multivariate analysis, factors significantly associated with treatment failure were living alone condition (OR=4.302; 95%IC=1.254-16.257; p=0.034) and RBV plasma level <1800ng/mL at 2weeks (OR=4.970; 95%IC=1.405-17.565; p=0.009). Considering a pharmacogenetic-guided approach, dual therapy with PEG-IFN and RBV can be considered a reliable option for patients ineligible for IFN-free treatments, who are motivated and well informed about all the aspects related to PEG-IFN administration.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Interleucinas/genética , Cirrose Hepática/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Expressão Gênica , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C Crônica/genética , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Interferons , Interleucinas/imunologia , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
AIM: Vitamin D modulates biological processes; an influence of vitamin D levels and genetic variants was identified concerning hepatitis B virus infection. We evaluated the role of some SNPs of vitamin D pathway genes in some clinical features of hepatitis B affected patients treated with pegylated interferon. METHODS: We investigated SNPs in IL-28B, CYP27B1, CYP27A1, CYP24A1, VDBP and VDR genes, through real-time PCR. RESULTS: VDRApaI SNP was associated to viral load and HBsAg presence at different timings. In logistic regression analyses, VDRApaI AA genotype predicted baseline viral load >6 Log IU/ml (marker of nonresponse), and both virological and biochemical responses. CONCLUSION: Pharmacogenetic data could help physicians in the prediction of patients with higher probability to achieve a good response.
Assuntos
Antivirais/uso terapêutico , Antígenos E da Hepatite B/genética , Interferon-alfa/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Vitamina D/genética , Adulto , Antivirais/farmacologia , Estudos de Coortes , Feminino , Hepatite B/sangue , Hepatite B/tratamento farmacológico , Hepatite B/genética , Antígenos E da Hepatite B/sangue , Humanos , Interferon-alfa/farmacologia , Masculino , Pessoa de Meia-Idade , Receptores de Calcitriol/sangue , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do Tratamento , Vitamina D/sangueRESUMO
AIM: Mixed cryoglobulinemia (MC) is an extra hepatic hepatitis C virus related problem and different studies suggested genetics' role in predicting this complication. We evaluated the influence of SNPs in IL-28B, SLC29A1, SLC28A2, NT5C2, HNF4 and ABCB1 genes in MC prediction. PATIENTS & METHODS: SNPs were evaluated through real-time PCR. RESULTS: ABCB1 (gene encoding P-glycoprotein) 3435C>T SNP was associated with MC presence (p = 0.034): related to T allele carriers (CC vs CT/TT), we reached a p-value of 0.013. In the logistic regression analysis baseline viral load >600.000 IU/ml (p < 001), IL28B rs8099917/rs12979860 TT/CC (p < 0.001), NT5 (gene encoding for 5' nucleotidase) 153 TC (p = 0.012) and ABCB1 3435 CT/TT (p = 0.034) genotypes predicted MC presence. CONCLUSION: These data could help clinicians to identify patients with higher probability to show MC extra hepatic complication.
Assuntos
Crioglobulinemia/epidemiologia , Crioglobulinemia/genética , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/genética , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único/genética , Adulto , Crioglobulinemia/diagnóstico , Feminino , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy decreases the progression risk of non-muscle-invasive bladder cancer, but potentially yields a broad spectrum of side effects. We report the case of a 73-year-old man affected by miliary pulmonary BCG infection, whose microbiological diagnosis was probably hindered by empiric fluoroquinolones, focusing on imaging and clinical work-up.
Assuntos
Vacina BCG/efeitos adversos , Imunoterapia/efeitos adversos , Mycobacterium bovis/patogenicidade , Tuberculose Miliar/etiologia , Tuberculose Pulmonar/etiologia , Idoso , Antituberculosos/uso terapêutico , Líquido da Lavagem Broncoalveolar/microbiologia , Carcinoma de Células de Transição/terapia , Diagnóstico Tardio , Febre de Causa Desconhecida/microbiologia , Humanos , Masculino , Mycobacterium bovis/isolamento & purificação , Ofloxacino/uso terapêutico , Escarro/microbiologia , Tuberculose Miliar/diagnóstico , Tuberculose Miliar/tratamento farmacológico , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/tratamento farmacológico , Neoplasias da Bexiga Urinária/terapiaRESUMO
To date, the new standard for treatment of chronic hepatitis C is based on the administration of novel direct acting antivirals. Among these, sofosbuvir, simeprevir, daclatasvir, ledipasvir, dasabuvir, ombitasvir and paritaprevir already entered the clinical use. Anyway, since few pharmacokinetic studies have been conducted on these drugs in a "real life" context poor knowledge is available about their optimal therapeutic range. Without this background, therapeutic drug monitoring is not applicable for treatment optimization. Up to now, a few methods are reported to quantify these drugs in human plasma, and none of them in a simultaneous way. The aim of this work was to develop and validate a simple, fast and cheap, but still reliable UHPLC-MS/MS method for the quantification of these drugs, feasible for a clinical routine use. Solid phase extraction was performed using HLB C18 96-well plates. Chromatographic separation was performed on a BEH C18 1.7µm, 2.1mm×50mm column, settled at 50°C, with a gradient run of two mobile phases: ammonium acetate 5mM (pH 9.5) and acetonitrile, with a flow rate of 0.4mL/min for 5min. Tandem-mass detection was carried out in positive electrospray ionization mode. Both inter and intraday imprecision and inaccuracy were below 15%, as required by FDA guidelines, while both recoveries and matrix effects resulted within the acceptance criteria. The method was tested on 80 patients samples with good performance. Being robust, simple and fast and requiring a low plasma volume, this method resulted eligible for a clinical routine use.
Assuntos
Antivirais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Calibragem , Humanos , Limite de Detecção , Reprodutibilidade dos TestesRESUMO
The standard-of-care for the treatment of genotype-1 chronic hepatitis C is based on the combination of direct acting antivirals, such as boceprevir and telaprevir, with ribavirin and pegylated-interferon alfa. These triple regimens give a higher response rate than dual therapy, but on the other hand show a more than 10% higher rate of anaemia. Not enough focus has been given to the interaction between telaprevir and RBV. In this work, we aimed to study and deepen this relationship by comparing ribavirin plasma and intra-erythrocytic concentrations at one month of triple and dual therapy (17 vs. 119 patients). Moreover, we determined telaprevir isomers concentrations and tested them for correlation with ribavirin concentrations and haemoglobin loss at one month of treatment. Finally, all drugs concentration data were tested for their correlation with the renal function during treatment. The comparisons of ribavirin concentration and toxicity data were repeated on a sub-group of 9 patients who had been treated 1 year before with dual therapy and then re-treated with triple therapy. The observed ribavirin plasma and intra-erythrocytic concentrations in triple therapy were significantly higher compared to dual therapy, both in whole group and sub-group comparison. Ribavirin concentrations were significantly correlated to the haemoglobin loss and telaprevir-S isomer concentrations (r(2)=0.317 P(value)=0.023 and r(2)=0.388 P(value)=0.008, respectively). Renal function had a significant decrease from the baseline value, but was not significantly correlated with drugs concentrations. These results highlight for the first time that, in the context of triple therapy with telaprevir, ribavirin exposure is related to the telaprevir-S isomer plasma concentration. We conclude that the addition of telaprevir to the dual therapy increases ribavirin exposure and haemoglobin loss: this effect could probably be managed through the therapeutic drug monitoring of ribavirin and telaprevir-S concentrations.