RESUMO
Tuberculosis (TB) remains one of the leading global causes of mortality. Several methods have been established to detect anti-TB agents in human plasma and serum. However, there is a notable absence of studies analyzing TB drugs in urine. Thus, our objective was to validate a method for quantifying first-line anti-TB agents: isoniazid (INH), pyrazinamide (PZA), ethambutol (ETH), and rifampicin (RIF), along with its metabolite 25-desacetylrifampicin, and degradation products: rifampicin quinone and 3-formyl-rifampicin in 10 µL of urine. Chromatographic separation was achieved using a Kinetex Polar C18 analytical column with gradient elution (5 mM ammonium acetate and acetonitrile with 0.1% formic acid). Mass spectrometry detection was carried out using a triple-quadrupole tandem mass spectrometer operating in positive ion mode. The lower limit of quantification (LLOQ) was 0.5 µg/mL for INH, PZA, ETH, and RIF, and 0.1 µg/mL for RIF's metabolites and degradation products. The method was validated following FDA guidance criteria and successfully applied to the analysis of the studied compounds in urine of TB patients. Additionally, we conducted a stability study of the anti-TB agents under various pH and temperature conditions to mimic the urine collection process in different settings (peripheral clinics or central laboratories).
Assuntos
Monitoramento de Medicamentos , Rifampina , Humanos , Rifampina/uso terapêutico , Cromatografia Líquida , Espectrometria de Massa com Cromatografia Líquida , Espectrometria de Massas em Tandem , Antituberculosos/uso terapêutico , EtambutolRESUMO
Variable pharmacokinetics of rifampin in tuberculosis (TB) treatment can lead to poor outcomes. Urine spectrophotometry is simpler and more accessible than recommended serum-based drug monitoring, but its optimal efficacy in predicting serum rifampin underexposure in adults with TB remains uncertain. Adult TB patients in New Jersey and Virginia receiving rifampin-containing regimens were enrolled. Serum and urine samples were collected over 24 h. Rifampin serum concentrations were measured using validated liquid chromatography-tandem mass spectrometry, and total exposure (area under the concentration-time curve) over 24 h (AUC0-24) was determined through noncompartmental analysis. The Sunahara method was used to extract total rifamycins, and rifampin urine excretion was measured by spectrophotometry. An analysis of 58 eligible participants, including 15 (26%) with type 2 diabetes mellitus, demonstrated that urine spectrophotometry accurately identified subtarget rifampin AUC0-24 at 0-4, 0-8, and 0-24 h. The area under the receiver operator characteristic curve (AUC ROC) values were 0.80 (95% CI 0.67-0.90), 0.84 (95% CI 0.72-0.94), and 0.83 (95% CI 0.72-0.93), respectively. These values were comparable to the AUC ROC of 2 h serum concentrations commonly used for therapeutic monitoring (0.82 [95% CI 0.71-0.92], P = 0.6). Diabetes status did not significantly affect the AUC ROCs for urine in predicting subtarget rifampin serum exposure (P = 0.67-0.92). Spectrophotometric measurement of urine rifampin excretion within the first 4 or 8 h after dosing is a simple and cost-effective test that accurately predicts rifampin underexposure. This test provides critical information for optimizing tuberculosis treatment outcomes by facilitating appropriate dose adjustments.
Assuntos
Diabetes Mellitus Tipo 2 , Tuberculose , Adulto , Humanos , Rifampina/farmacocinética , Antituberculosos/farmacocinética , Estudos Prospectivos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológicoRESUMO
BACKGROUND: COVID-19 is a multi-system infection with emerging evidence-based antiviral and anti-inflammatory therapies to improve disease prognosis. However, a subset of patients with COVID-19 signs and symptoms have repeatedly negative RT-PCR tests, leading to treatment hesitancy. We used comparative serology early in the COVID-19 pandemic when background seroprevalence was low to estimate the likelihood of COVID-19 infection among RT-PCR negative patients with clinical signs and/or symptoms compatible with COVID-19. METHODS: Between April and October 2020, we conducted serologic testing of patients with (i) signs and symptoms of COVID-19 who were repeatedly negative by RT-PCR ('Probables'; N = 20), (ii) signs and symptoms of COVID-19 but with a potential alternative diagnosis ('Suspects'; N = 15), (iii) no signs and symptoms of COVID-19 ('Non-suspects'; N = 43), (iv) RT-PCR confirmed COVID-19 patients (N = 40), and (v) pre-pandemic samples (N = 55). RESULTS: Probables had similar seropositivity and levels of IgG and IgM antibodies as propensity-score matched RT-PCR confirmed COVID-19 patients (60.0% vs 80.0% for IgG, p-value = 0.13; 50.0% vs 72.5% for IgM, p-value = 0.10), but multi-fold higher seropositivity rates than Suspects and matched Non-suspects (60.0% vs 13.3% and 11.6% for IgG; 50.0% vs 0% and 4.7% for IgM respectively; p-values < 0.01). However, Probables were half as likely to receive COVID-19 treatment than the RT-PCR confirmed COVID-19 patients with similar disease severity. CONCLUSIONS: Findings from this study indicate a high likelihood of acute COVID-19 among RT-PCR negative with typical signs/symptoms, but a common omission of COVID-19 therapies among these patients. Clinically diagnosed COVID-19, independent of RT-PCR positivity, thus has a potential vital role in guiding treatment decisions.
Assuntos
Tratamento Farmacológico da COVID-19 , Anticorpos Antivirais , Humanos , Imunoglobulina M , Pandemias , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Estudos SoroepidemiológicosRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a global pandemic. Clinical characteristics regarding secondary infections in patients with COVID-19 have been reported, but detailed microbiology, risk factors, and outcomes of secondary bloodstream infections (sBSIs) in patients with severe COVID-19 have not been well described. METHODS: We performed a multicenter case-control study including all hospitalized patients diagnosed with severe COVID-19 and blood cultures drawn from 1 March 2020 to 7 May 2020 at 3 academic medical centers in New Jersey. Data collection included demographics, clinical and microbiologic variables, and patient outcomes. Risk factors and outcomes were compared between cases (sBSI) and controls (no sBSI). RESULTS: A total of 375 hospitalized patients were included. There were 128 sBSIs during the hospitalization. For the first set of positive blood cultures, 117 (91.4%) were bacterial and 7 (5.5%) were fungal. Those with sBSI were more likely to have altered mental status, lower mean percentage oxygen saturation on room air, have septic shock, and be admitted to the intensive care unit compared with controls. In-hospital mortality was higher in those with an sBSI versus controls (53.1% vs 32.8%, Pâ =â .0001). CONCLUSIONS: We observed that hospitalized adult patients with severe COVID-19 and sBSI had a more severe initial presentation, prolonged hospital course, and worse clinical outcomes. To maintain antimicrobial stewardship principles, further prospective studies are necessary to better characterize risk factors and prediction modeling to better understand when to suspect and empirically treat for sBSIs in severe COVID-19.
Assuntos
COVID-19 , Coinfecção , Sepse , Adulto , Estudos de Casos e Controles , Hospitalização , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2RESUMO
BACKGROUND: Fluoroquinolones and second-line injectable drugs are the backbone of treatment regimens for multidrug-resistant tuberculosis, and resistance to these drugs defines extensively drug-resistant tuberculosis. We assessed the accuracy of an automated, cartridge-based molecular assay for the detection, directly from sputum specimens, of Mycobacterium tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid. METHODS: We conducted a prospective diagnostic accuracy study to compare the investigational assay against phenotypic drug-susceptibility testing and DNA sequencing among adults in China and South Korea who had symptoms of tuberculosis. The Xpert MTB/RIF assay and sputum culture were performed. M. tuberculosis isolates underwent phenotypic drug-susceptibility testing and DNA sequencing of the genes katG, gyrA, gyrB, and rrs and of the eis and inhA promoter regions. RESULTS: Among the 308 participants who were culture-positive for M. tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 µg per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 µg per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 µg per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater. CONCLUSIONS: This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with tuberculosis. (Funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Ministry of Science and Technology of China; ClinicalTrials.gov number, NCT02251327 .).
Assuntos
Antituberculosos/farmacologia , DNA Bacteriano/análise , Farmacorresistência Bacteriana Múltipla/genética , Testes de Sensibilidade Microbiana/métodos , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Sistemas Automatizados de Assistência Junto ao Leito , Análise de Sequência de DNA , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoglicosídeos/farmacologia , Antituberculosos/uso terapêutico , China , Feminino , Fluoroquinolonas/farmacologia , Humanos , Isoniazida/farmacologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Estudos Prospectivos , República da Coreia , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto JovemRESUMO
Background: Among adults with signs and symptoms of pulmonary tuberculosis (TB), recognition of transmissible TB has implications for airborne infection isolation and public health activities. Sputum smear-negative TB patients account for around one-fifth of tuberculosis transmission. The tuberculosis transmission risk of TB patients with negative results on nucleic acid amplification test (NAAT) of respiratory specimens has not been established. We sought to estimate the tuberculosis transmission risk of NAAT-negative TB patients. Methods: We retrospectively reviewed Maryland TB program data collected from 2004 to 2009, during which time NAAT using the Mycobacterium Tuberculosis Direct Test (MTD) was performed routinely. Patients with sputum Mycobacterium tuberculosis (M.tb) isolates having matching genotypes were assigned to clusters. Transmission sequence was approximated by collection order of individuals' first culture-positive specimens. Minimum transmission risks of NAAT (MTD)-negative TB patients and of smear-negative TB patients were estimated based on individuals' positions within clusters. Results: Among 809 patients with culture-confirmed TB, M.tb genotypes were available for 782 (96.7%). For NAA-negative TB patients, the minimum transmission risk estimate was 5.1% (95% CI 0-11.4). For smear-negative TB patients, the minimum transmission risk estimate was 11.2% (95% CI 7.2-15.3). Conclusions: Minimum transmission risk of NAAT-negative TB patients was lower than that of smear-negative TB patients. However, transmission risk of NAA-negative TB patients appears to not be negligible.
Assuntos
Mycobacterium tuberculosis/isolamento & purificação , Escarro/microbiologia , Tuberculose Pulmonar/transmissão , Adulto , Análise por Conglomerados , Feminino , Genótipo , Humanos , Masculino , Maryland , Prontuários Médicos , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Técnicas de Amplificação de Ácido Nucleico , Estudos Retrospectivos , Células-Tronco , Tuberculose Pulmonar/diagnóstico , Adulto JovemRESUMO
BACKGROUND: Autosplenectomy, as a result of sickle cell disease, is an important risk factor for severe malaria. While molecular methods are helpful in providing rapid and accurate infection detection and species identification, the effect of hyposplenism on result interpretation during the course of infection should be carefully considered. CASE PRESENTATION: A 32-year old autosplenectomized Nigerian male with severe sickle cell disease was referred to the National Institutes of Health for allogenic hematopoietic stem cell transplant. Despite testing negative for malaria by both smear and PCR 2 weeks after arrival in the USA, the patient developed fever and diffuse bilateral lower rib cage and upper abdominal pain 2 weeks later and subsequently tested positive for Plasmodium falciparum. Parasitaemia was tracked over time by microscopy and nucleic acid tests to evaluate the therapeutic response in the setting of hyposplenism. The patient showed prompt resolution of patent infection by microscopy but remained positive by molecular methods for > 30 days after treatment initiation. CONCLUSION: While molecular testing can provide sensitive Plasmodium nucleic acid detection, the persistence of Plasmodium nucleic acids following adequate treatment in functionally asplenic patients can lead to a diagnostic dilemma. In such patients, clinical response and peripheral blood smears should guide patient management following treatment. Nonetheless, in pre-transplant patients at high-risk for pre-existing Plasmodium infections, highly sensitive molecular assays can be useful to rule out infection prior to transplantation.
Assuntos
Anemia Falciforme/complicações , Antimaláricos/uso terapêutico , DNA de Protozoário/sangue , Monitoramento de Medicamentos/métodos , Malária Falciparum/diagnóstico , Malária Falciparum/patologia , Adulto , Humanos , Malária Falciparum/tratamento farmacológico , Masculino , Microscopia , Ácidos Nucleicos , Reação em Cadeia da Polimerase , Fatores de Tempo , Estados UnidosRESUMO
Interferon-gamma (IFNγ) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFNγ-neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFNγ contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions.
Assuntos
Antibacterianos/efeitos adversos , Anticorpos Neutralizantes/biossíntese , Autoanticorpos/sangue , Interferon gama/imunologia , Tuberculose Miliar/imunologia , Antibacterianos/administração & dosagem , Autoanticorpos/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Inflamação/imunologia , Inflamação/microbiologia , Interferon gama/sangue , Pessoa de Meia-Idade , Tuberculose Miliar/tratamento farmacológico , Tuberculose Miliar/etnologia , Estados UnidosRESUMO
Fever and leukocytosis have many possible etiologies in injection drug users. We present a case of a 22-year-old woman with fever and leukocytosis that were presumed secondary to cotton fever, a rarely recognized complication of injection drug use, after an extensive workup. Cotton fever is a benign, self-limited febrile syndrome characterized by fevers, leukocytosis, myalgias, nausea and vomiting, occurring in injection drug users who filter their drug suspensions through cotton balls. While this syndrome is commonly recognized amongst the injection drug user population, there is a paucity of data in the medical literature. We review the case presentation and available literature related to cotton fever.
Assuntos
Febre/etiologia , Leucocitose/etiologia , Participação do Paciente , Abuso de Substâncias por Via Intravenosa/complicações , Feminino , Febre/diagnóstico , Humanos , Leucocitose/diagnóstico , Abuso de Substâncias por Via Intravenosa/diagnóstico , Adulto JovemRESUMO
BACKGROUND: Xpert MTB/RIF Ultra (Ultra) is an automated molecular test for the detection of Mycobacterium tuberculosis in sputum. We compared the sensitivity of Ultra to that of mycobacterial growth indicator tube (MGIT) liquid culture, considered the most sensitive assay in routine clinical use. METHODS: In this prospective, multicentre, cross-sectional diagnostic accuracy study, we used a non-inferiority design to assess whether the sensitivity of a single Ultra test was non-inferior to that of a single liquid culture for detection of M tuberculosis in sputum. We enrolled adults (age ≥18 years) with pulmonary tuberculosis symptoms in 11 countries and each adult provided three sputum specimens with a minimum volume of 2 mL over 2 days. Ultra was done directly on sputum 1, and Ultra and MGIT liquid culture were done on resuspended pellet from sputum 2. Results of MGIT and solid media cultures done on sputum 3 were considered the reference standard. The pre-defined non-inferiority margin was 5·0%. FINDINGS: Between Feb 18, 2016, and Dec 4, 2019, we enrolled 2906 participants. 2600 (89%) participants were analysed, including 639 (25%) of 2600 who were positive for tuberculosis by the reference standard. Of the 2357 included in the non-inferiority analysis, 877 (37%) were HIV-positive and 984 (42%) were female. Sensitivity of Ultra performed directly on sputum 1 was non-inferior to that of sputum 2 MGIT culture (MGIT 91·1% vs Ultra 91·9%; difference -0·8 percentage points; 95% CI -2·8 to 1·1). Sensitivity of Ultra performed on sputum 2 pellet was also non-inferior to that of sputum 2 MGIT (MGIT 91·1% vs Ultra 91·9%; difference -0·8 percentage points; -2·7 to 1·0). INTERPRETATION: For the detection of M tuberculosis in sputum from adults with respiratory symptoms, there was no difference in sensitivity of a single Ultra test to that of a single MGIT culture. Highly sensitive, rapid molecular approaches for M tuberculosis detection, combined with advances in genotypic methods for drug resistance detection, have potential to replace culture. FUNDING: US National Institute of Allergy and Infectious Diseases.
Assuntos
Mycobacterium tuberculosis , Escarro , Tuberculose Pulmonar , Humanos , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crescimento & desenvolvimento , Escarro/microbiologia , Adulto , Feminino , Masculino , Estudos Transversais , Estudos Prospectivos , Pessoa de Meia-Idade , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/microbiologia , Sensibilidade e Especificidade , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Adulto Jovem , IdosoRESUMO
UNLABELLED: A cluster of 3 facial Mycobacterium chelonae infections occurred after cosmetic dermal filler injections at a plastic surgery clinic. Pulsed-field gel electrophoresis showed that M chelonae isolated from the clinic tap water were identical to the patient wound isolates. Review of injection procedures identified application of nonsterile ice to the skin prior to injection as a possible source of M chelonae. Surveys of regional laboratories and a national plastic surgery listserv identified no other cases related to the injection of this brand of dermal filler. This is the first report of cutaneous M chelonae infections following the injection of dermal fillers. It adds to a growing body of literature on postinjection M chelonae infections and reinforces the importance of optimal skin disinfection steps prior to percutaneous procedures. LEVEL OF EVIDENCE: 5.
Assuntos
Técnicas Cosméticas/efeitos adversos , Infecções por Mycobacterium não Tuberculosas/etiologia , Mycobacterium chelonae/isolamento & purificação , Técnicas Cosméticas/normas , Eletroforese em Gel de Campo Pulsado , Face , Feminino , Humanos , Gelo/normas , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Microbiologia da Água , Abastecimento de ÁguaRESUMO
Successful tuberculosis (TB) therapy requires achieving sufficient exposure to multiple drugs. Limited stability of several first-line anti-TB drugs might compromise reliable therapeutic drug monitoring (TDM). We developed and validated a sensitive and selective UPLC-MS/MS method for simultaneous quantification of isoniazid (INH), pyrazinamide (PZA), rifampicin (RIF), its metabolite 25-desacetylrifampicin and degradation products: rifampicin quinone and 3-formyl-rifampicin. Analysis was completed from a very small plasma volume (20 µL) using only protein precipitation with methanol. Chromatographic separation was achieved on a Kinetex Polar C18 column (2.6 µm; 150 × 3 mm) with a mobile phase consisting of 5 mM ammonium acetate and acetonitrile, both containing 0.1 % formic acid, in gradient elution. The analytes were detected using a positive ionization mode by multiple reaction monitoring. The LLOQ for RIF and its degradation products was 0.1 µg/mL, 0.05 µg/mL for INH, and 0.2 µg/mL for PZA. The method was validated based on the FDA guidance. The application of the method was confirmed in the analysis of RIF, INH, and PZA, as well as RIF metabolism/degradation products in plasma samples of patients with TB. Based on the detailed stability study of the analyzed compounds at various storage conditions, we proposed recommendations for handling the plasma and serum samples in TDM and other pharmacokinetic studies.
Assuntos
Rifampina , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , AntituberculososRESUMO
Saliva has been a COVID-19 diagnostic specimen of interest due to its simple collection, scalability, and yield. Yet COVID-19 testing and estimates of the infectious period remain largely based on nasopharyngeal and nasal swabs. We sought to evaluate whether saliva testing captured prolonged presence of SARS-CoV-2 and potential infectiousness later in the disease course. We conducted an observational study of symptomatic COVID-19 patients at University Hospital in Newark, NJ. Paired saliva and nasal specimens from 96 patients were analyzed, including longitudinal analysis of paired observations from 28 of these patients who had multiple time-points. Saliva detected significantly more cases of COVID-19 beyond 5 days (86.1% [99/115] saliva vs 48.7% [56/115] nasal, p-value < 0.001), 9 days (79.4% [50/63] saliva vs 36.5% [23/63] nasal, p-value < 0.001) and 14 days (71.4% [20/28] saliva vs 32.1% [9/28] nasal, p-value = 0.010) of symptoms. Additionally, saliva yielded lower cycle thresholds across all time periods, indicative of higher viral loads in saliva. In the longitudinal analysis, a log-rank analysis indicated that the survival curve for saliva was significantly different from the curve for nasal swabs (p<0.001) with a median survival time for saliva of 18 days compared to 13 days for nasal swabs. We additionally performed saliva viral cultures among a similar COVID-19 patient cohort and noted patients with positive saliva viral cultures between 7 to 28 days of symptoms. Findings from this study suggest that SARS-CoV-2 RNA persists longer and in higher abundance in saliva compared to nasal swabs, with potential of prolonged propagating virus. Testing saliva may thus increase yield for detecting potentially infectious virus even beyond the first five days of symptomatic COVID-19.
Assuntos
COVID-19 , Doenças Transmissíveis , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , Teste para COVID-19 , Saliva , RNA Viral/genética , Manejo de Espécimes , NasofaringeRESUMO
BACKGROUND AND OBJECTIVE: Quantifying exposure to drugs for personalized dose adjustment is of critical importance in patients with tuberculosis who may be at risk of treatment failure or toxicity due to individual variability in pharmacokinetics. Traditionally, serum or plasma samples have been used for drug monitoring, which only poses collection and logistical challenges in high-tuberculosis burden/low-resourced areas. Less invasive and lower cost tests using alternative biomatrices other than serum or plasma may improve the feasibility of therapeutic drug monitoring. METHODS: A systematic review was conducted to include studies reporting anti-tuberculosis drug concentration measurements in dried blood spots, urine, saliva, and hair. Reports were screened to include study design, population, analytical methods, relevant pharmacokinetic parameters, and risk of bias. RESULTS: A total of 75 reports encompassing all four biomatrices were included. Dried blood spots reduced the sample volume requirement and cut shipping costs whereas simpler laboratory methods to test the presence of drug in urine can allow point-of-care testing in high-burden settings. Minimal pre-processing requirements with saliva samples may further increase acceptability for laboratory staff. Multi-analyte panels have been tested in hair with the capacity to test a wide range of drugs and some of their metabolites. CONCLUSIONS: Reported data were mostly from small-scale studies and alternative biomatrices need to be qualified in large and diverse populations for the demonstration of feasibility in operational settings. High-quality interventional studies will improve the uptake of alternative biomatrices in guidelines and accelerate implementation in programmatic tuberculosis treatment.
Assuntos
Monitoramento de Medicamentos , Tuberculose , Humanos , Monitoramento de Medicamentos/métodos , Antituberculosos/farmacocinética , Tuberculose/tratamento farmacológicoRESUMO
At least a third of tuberculosis (TB) cases remain undiagnosed, disproportionately so in children and adolescents, which is hampering global elimination goals. Prolonged symptom duration presents a high-risk scenario for childhood TB in endemic areas, but the prolonged period of symptoms and its impact on educational attainment are rarely documented. Using a mixed method approach, we aimed to quantify the duration of respiratory symptoms and describe their impact on education among children from a rural area of Tanzania. We used data from a prospectively enrolled cohort of children and adolescents aged 4-17 years in rural Tanzania at the start of active TB treatment. We report on the cohort's baseline characteristics and explore the correlation between duration of symptoms and other variables. In-depth qualitative interviews were designed on the basis of a grounded theory approach to explore the impact of TB on educational attainment among school-aged children. In this cohort, children and adolescents diagnosed with TB experienced symptoms for a median of 85 days (interquartile range: 30, 231 days) prior to treatment initiation. In addition, 56 participants (65%) had a TB exposure in the household. Of the 16 families with school-aged children who were interviewed, 15 (94%) reported a significant negative impact of TB on the schooling of their children. Children in this cohort experienced a long duration of TB symptoms; the extent of illness impacted absenteeism at school. Screening initiatives for households affected by TB may lead to a shortened duration of symptoms and may minimize the impact on school attendance.
Assuntos
Tuberculose , Criança , Humanos , Adolescente , Tanzânia/epidemiologia , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Escolaridade , Instituições Acadêmicas , Características da FamíliaRESUMO
Distinct from quantifying the economic sequelae of tuberculosis (TB) in adults, data are scarce regarding lived experiences of youth and their caregivers seeking and sustaining TB treatment in low income communities. Children ages 4-17 diagnosed with TB and their caregivers were recruited from rural and semi-urban northern Tanzania. Using a grounded theory approach, a qualitative interview guide was developed, informed by exploratory research. Twenty-four interviews were conducted in Kiswahili, audio-recorded and analyzed for emerging and consistent themes. Dominant themes found were socioemotional impacts of TB on households, including adverse effects on work productivity, and facilitators and obstacles to TB care, including general financial hardship and transportation challenges. The median percentage of household monthly income spent to attend a TB clinic visit was 34% (minimum: 1%, maximum: 220%). The most common solutions identified by caregivers to mitigate adverse impacts were transportation assistance and nutrition supplementation. To end TB, healthcare systems must acknowledge the total financial burden shouldered by low wealth families seeking pediatric TB care, provide consultations and medications locally, and increase access to TB-specific communal funds to mitigate burdens such as inadequate nutrition.Trial registration: planned sub-study of the registered prospective study, NCT05283967.Trial registration: ClinicalTrials.gov identifier: NCT05283967.
Assuntos
Cuidadores , Tuberculose , Adulto , Adolescente , Humanos , Criança , Pré-Escolar , Tanzânia , Estudos Prospectivos , Renda , Tuberculose/diagnósticoRESUMO
OBJECTIVE: Pharmacokinetic variability drives tuberculosis (TB) treatment outcomes but measurement of serum drug concentrations for personalised dosing is inaccessible for children in TB-endemic settings. We compared rifampin urine excretion for prediction of a serum target associated with treatment outcome. DESIGN: Prospective diagnostic accuracy study. SETTING: Inpatient wards and outpatient clinics, northern Tanzania. PATIENTS: Children aged 4-17 years were consecutively recruited on initiation of WHO-approved treatment regimens. INTERVENTIONS: Samples were collected after directly observed therapy at least 2 weeks after initiation in the intensive phase: serum at pre-dose and 1, 2 and 6 hours post-dose, later analysed by liquid chromatography-tandem mass spectrometry for calculation of rifampin total exposure or area under the concentration time curve (AUC0-24); urine at post-dose intervals of 0-4, 4-8 and 8-24 hours, with rifampin excretion amount measured onsite by spectrophotometry. MAIN OUTCOME MEASURES: Receiver operating characteristic (ROC) curve for percentage of rifampin dose excreted in urine measured by spectrophotometry to predict serum rifampin AUC0-24 target of 31.7 mg*hour/L. RESULTS: 89 children, 52 (58%) female, with median age of 9.1 years, had both serum and urine collection. Only 59 (66%) reached the serum AUC0-24 target, reflected by a range of urine excretion patterns. Area under the ROC curve for percentage of rifampin dose excreted in urine over 24 hours predicting serum AUC0-24 target was 69.3% (95% CI 56.7% to 81.8%), p=0.007. CONCLUSIONS: Urine spectrophotometry correlated with a clinically relevant serum target for rifampin, representing a step toward personalised dosing for children in TB-endemic settings.
Assuntos
Rifampina , Tuberculose , Humanos , Criança , Feminino , Masculino , Rifampina/uso terapêutico , Rifampina/farmacocinética , Antituberculosos/uso terapêutico , Antituberculosos/farmacocinética , Estudos Prospectivos , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) is an immunoinflammatory and hypercoagulable state that contributes to respiratory distress, multi-organ dysfunction, and mortality. Dipyridamole, by increasing extracellular adenosine, has been postulated to be protective for COVID-19 patients through its immunosuppressive, anti-inflammatory, anti-coagulant, vasodilatory, and anti-viral actions. Likewise, low-dose aspirin has also demonstrated protective effects for COVID-19 patients. This study evaluated the effect of these two drugs formulated together as Aggrenox in hospitalized COVID-19 patients. METHODS: In an open-label, single site randomized controlled trial (RCT), hospitalized COVID-19 patients were assigned to adjunctive Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally) with standard of care treatment compared to standard of care treatment alone. Primary endpoint was illness severity according to changes on the eight-point COVID ordinal scale, with levels of 1 to 8 where higher scores represent worse illness. Secondary endpoints included all-cause mortality and respiratory failure. Outcomes were measured through days 14, 28, and/or hospital discharge. RESULTS: From October 1, 2020 to April 30, 2021, a total of 98 patients, who had a median [IQR] age of 57 [47, 62] years and were 53.1% (n = 52) female, were randomized equally between study groups (n = 49 Aggrenox plus standard of care versus n = 49 standard of care alone). No clinically significant differences were found between those who received adjunctive Aggrenox and the control group in terms of illness severity (COVID ordinal scale) at days 14 and 28. The overall mortality through day 28 was 6.1% (3 patients, n = 49) in the Aggrenox group and 10.2% (5 patients, n = 49) in the control group (OR [95% CI]: 0.40 [0.04, 4.01], p = 0.44). Respiratory failure through day 28 occurred in 4 (8.3%, n = 48) patients in the Aggrenox group and 7 (14.6%, n = 48) patients in the standard of care group (OR [95% CI]: 0.21 [0.02, 2.56], p = 0.22). A larger decrease in the platelet count and blood glucose levels, and larger increase in creatinine and sodium levels within the first 7 days of hospital admission were each independent predictors of 28-day mortality (p < 0.05). CONCLUSION: In this study of hospitalized patients with COVID-19, while the outcomes of COVID illness severity, odds of mortality, and chance of respiratory failure were better in the Aggrenox group compared to standard of care alone, the data did not reach statistical significance to support the standard use of adjuvant Aggrenox in such patients.