Is the Pharmacokinetics of First-Line Anti-TB Drugs a Cause of High Mortality Rates in TB Patients Admitted to the ICU? A Non-Compartmental Pharmacokinetic Analysis.

BACKGROUND: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rifampin, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality. METHODS: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis. RESULTS: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rifampin, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients. CONCLUSIONS: ICU patients had a lower clearance and volume of distribution for rifampin, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.

Systematic review with network meta-analysis on the treatments for latent tuberculosis infection in children and adolescents.

BACKGROUND: We aimed to synthesize the evidence on the efficacy and safety of different treatment regimens for latent tuberculosis infection (LTBI) in children and adolescents. METHODS: A systematic review with network meta-analysis was performed (CRD142933). Searches were conducted in Pubmed and Scopus (Nov-2021). Randomized controlled trials comparing treatments for LTBI (patients up to 15 years), and reporting data on the incidence of the disease, death or adverse events were included. Networks using the Bayesian framework were built for each outcome of interest. Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Rank probabilities were calculated via the surface under the cumulative ranking analysis (SUCRA) (Addis-v.1.16.8). GRADE approach was used to rate evidence's certainty. RESULTS: Seven trials (n = 8696 patients) were included. Placebo was significantly associated with a higher incidence of tuberculosis compared to all active therapies. Combinations of isoniazid (15-25 mg/kg/week) plus rifapentine (300-900 mg/week), followed by isoniazid plus rifampicin (10 mg/kg/day) were ranked as best approaches with lower probabilities of disease incidence (10% and 19.5%, respectively in SUCRA) and death (20%). Higher doses of isoniazid monotherapy were significantly associated to more deaths (OR 18.28, 95% ICr [1.02, 48.60] of 4-6 mg/kg/day vs. 10 mg/kg/3x per week). CONCLUSIONS: Combined therapies of isoniazid plus rifapentine or rifampicin for short-term periods should be used as the first-line approach for treating LTBI in children and adolescents. The use of long-term isoniazid as monotherapy and at higher doses should be avoided for this population.

Population Pharmacokinetic Model of Piperacillin in Critically Ill Patients and Describing Interethnic Variation Using External Validation.

Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients.

Efficacy and safety of daily treatments for drug-susceptible pulmonary tuberculosis: a systematic review and network meta-analysis.

OBJECTIVES: To evaluate and update the evidence on the comparative efficacy and safety of antimicrobial drugs regimens for treating pulmonary drug-susceptible tuberculosis (DS-TB). METHODS: A systematic review was performed with searches in PubMed and Scopus (PROSPERO-CRD42019141463). We included randomised controlled trials comparing the effect of any antimicrobial regimen lasting at least 2 weeks. The outcomes of interest were culture conversion and incidence of adverse events. Bayesian network meta-analyses and surface under the cumulative ranking curve (SUCRA) analyses were performed. Results were reported as odds ratio with 95% credibility intervals. KEY FINDINGS: Fifteen studies were included the meta-analysis (n = 7560 patients). No regimen was statistically more effective than the WHO standard approach (rifampicin, isoniazid, ethambutol, and pyrazinamide). The use of rifapentine 450 mg instead of rifampicin in the standard regimen demonstrated to be statistically safer than all other options for serious adverse events (e.g. hepatotoxicity, arthralgia) (OR ranging from 0.0 [Crl 0.00-0.04] to 0.0 [0.00-0.97]; SUCRA probabilities of 10%). Therapies containing rifapentine (Rp1500HEZ, Rp900HEZ) and moxifloxacin (RMEZ, RHMZ) are effective regarding culture conversion, but statistical uncertainty on their safety profile exists. CONCLUSION: The WHO standard regimen remains an overall effective and safe alternative for DS-TB. For intensive phase treatments, drugs combinations with rifapentine and moxifloxacin seem to reduce treatment duration while maintaining efficacy.

Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study.

BACKGROUND: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. METHODS: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. RESULTS: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. CONCLUSIONS: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures.

Examination of respiratory specimens improves microbiological diagnosis of patients with presumptive extrapulmonary tuberculosis.

OBJECTIVES: Bacteriological confirmation of extrapulmonary tuberculosis (EPTB) is challenging for several reasons: the paucibacillary nature of the sample; scarce resources, mainly in middle and low-income countries; the need for hospitalization; and unfavorable outcomes. We evaluated the diagnostic role of respiratory specimen examination prospectively in a cohort of patients with presumptive EPTB. METHODS: From July 2018 to January 2019, in a tuberculosis (TB)/HIV reference hospital, a cohort of 157 patients with presumed EPTB was evaluated. Xpert® MTB/RIF Ultra or a culture-positive result was considered for bacteriologically confirmed TB. RESULTS: Out of 157 patients with presumptive EPTB, 97 (62%) provided extrapulmonary and respiratory specimens and 60 (38%) extrapulmonary specimens only. Of the 60 patients with extrapulmonary samples, 5 (8%) were positive. Of those with respiratory and extrapulmonary samples, 27 (28%) were positive: 10 in both the respiratory and extrapulmonary samples, 6 in the extrapulmonary sample only, and 11 in the respiratory sample only. A respiratory specimen examination increased by 6-fold the chance of bacteriological confirmation of TB (odds ratio = 5.97 [1.11-47.17]). CONCLUSION: We conclude that respiratory samples should be examined in patients with presumptive EPTB.

Safety and efficacy of N-acetylcysteine in hospitalized patients with HIV-associated tuberculosis: An open-label, randomized, phase II trial (RIPENACTB Study).

Despite the availability of effective antimicrobials, tuberculosis (TB) is still a serious health threat. Mortality is even higher in people living with HIV who are diagnosed with TB. New therapies are needed to shorten the time required to cure TB and decrease fatality rates in this population. N-acetylcysteine (NAC) is a glutathione precursor and has shown recently in experimental setting to present in vitro and in vivo anti-mycobacterial activity. We test the hypothesis that NAC is safe, well tolerated and secondarily efficacious as adjunctive anti-TB therapy in hospitalized individuals with HIV-associated TB. Patients were enrolled sequentially in a tertiary care center, in the Brazilian Amazon. We performed a randomized, parallel group, single-center, open study trial of two arms, in hospitalized patients over 18 years of age, with microbiologically confirmed pulmonary TB in HIV: one with rifampicin, isoniazid, pyrazinamide and ethambutol at standard doses (Control Group), and a second in which NAC 600 mg bid for eight weeks was added (NAC Group). A total of 21 and 18 patients were enrolled to the Control Group and NAC Group, respectively. Adverse event rates were similar in the two arms. Our findings suggest that in the more critical population of hospitalized patients with HIV-associated TB, the use of NAC was not unsafe, despite the low sample size, and a potential impact on faster negative cultures needs to be further explored in larger studies.

LC-QToF-MS method for quantification of ethambutol, isoniazid, pyrazinamide and rifampicin in human plasma and its application.

In this research, we developed and validated a liquid chromatography coupled to mass spectrometry (LC-QToF-MS) method for simultaneous quantification of the anti-tuberculosis drugs ethambutol, isoniazid, pyrazinamide and rifampicin in human plasma. Plasma samples spiked with cimetidine (internal standard) were extracted using protein precipitation with acetonitrile containing 1% formic acid. Separation was performed using a C18 column under flow gradient conditions with water and acetonitrile, both containing 5 mm ammonium formate and 0.1% formic acid. The method was validated according to the ANVISA and US Food and Drug Administration guidelines for bioanalytical method validation. The calibration curve was linear over a concentration range of 0.2-5 µg ml-1 for ethambutol, 0.2-7.5 µg ml-1 for isoniazid, 1-40 µg ml-1 for pyrazinamide and 0.25-2 µg ml-1 for rifampicin, all with adequate precision and accuracy. The method was reproducible, selective and free of carryover and matrix effects. The validated LC-QToF-MS method was successfully applied to real samples and shown to be applicable to future therapeutic and pharmacokinetic monitoring studies.

Adjunct N-Acetylcysteine Treatment in Hospitalized Patients With HIV-Associated Tuberculosis Dampens the Oxidative Stress in Peripheral Blood: Results From the RIPENACTB Study Trial.

Tuberculosis (TB) still causes significant morbidity and mortality worldwide, especially in persons living with human immunodeficiency virus (HIV). This disease is hallmarked by persistent oxidative stress and systemic inflammation. N-acetylcysteine (NAC), a glutathione (GSH) precursor, has been shown in experimental models to limit Mycobacterium tuberculosis infection and disease both by suppression of the host oxidative response and through direct antimicrobial activity. In a recent phase II randomized clinical trial (RIPENACTB study), use of NAC as adjunct therapy during the first two months of anti-TB treatment was safe. Whether adjunct NAC therapy of patients with TB-HIV coinfection in the context of anti-TB treatment could directly affect pro-oxidation and systemic inflammation has not been yet formally demonstrated. To test this hypothesis, we leveraged existing data and biospecimens from the RIPENACTB trial to measure a number of surrogate markers of oxidative stress and of immune activation in peripheral blood of the participants at pre-treatment and at the day 60 of anti-TB treatment. Upon initiation of therapy, we found that the group of patients undertaking NAC exhibited significant increase in GSH levels and in total antioxidant status while displaying substantial reduction in lipid peroxidation compared to the control group. Only small changes in plasma concentrations of cytokines were noted. Pharmacological improvement of the host antioxidant status appears to be a reasonable strategy to reduce TB-associated immunopathology.

Early death by tuberculosis as the underlying cause in a state of Southern Brazil: Profile, comorbidities and associated vulnerabilities.

AIM: To know the profile of adults who died by tuberculosis as the main cause, the time interval between the diagnosis and death, associated comorbidities and vulnerabilities. METHOD: Observational study of secondary data regarding deaths by tuberculosis that occurred in the State of Paraná, Brazil, from 2008 to 2015. A linkage between the databases of mortality and tuberculosis notification system was conducted for data enrichment. Frequency tables, Exact Fisher test and Z test have identified statistical associations. RESULTS: Linkage points out 12.1% (115/944) of under-reporting in the 944 deaths identified. Early deaths accounted for 74.6% (705/944). The male sex (75.8%) was associated with the early death group. Almost half of the deaths reported in notification system (414/829) had one or more vulnerabilities. Early death were associated with respiratory system diseases and symptoms (p=0.0001) and mental and behavioral disorders (p=0.0001). CONCLUSION: High number of early deaths due TB indicate the need to seek out the respiratory symptomatic and use faster diagnostic methods. Strategies for treatment adherence, adequate monitoring of comorbidities and multisectorial support may prevent early and late death. The presence of vulnerabilities indicates that efforts beyond the health sector are needed in order to eliminate tuberculosis as public health problem.

Predictors of mortality among intensive care unit patients coinfected with tuberculosis and HIV.

OBJECTIVE: To identify factors predictive of mortality in patients admitted to the ICU with tuberculosis (TB)/HIV coinfection in the Manaus, Amazon Region. METHODS: This was a retrospective cohort study of TB/HIV coinfected patients over 18 years of age who were admitted to an ICU in the city of Manaus, Brazil, between January of 2011 and December of 2014. Sociodemographic, clinical, and laboratory variables were assessed. To identify factors predictive of mortality, we employed a Cox proportional hazards model. RESULTS: During the study period, 120 patients with TB/HIV coinfection were admitted to the ICU. The mean age was 37.0 ± 11.7 years. Of the 120 patients evaluated, 94 (78.3%) died and 62 (66.0%) of those deaths having occurred within the first week after admission. Data on invasive mechanical ventilation (IMV) and ARDS were available for 86 and 67 patients, respectively Of those 86, 75 (87.2%) underwent IMV, and, of those 67, 48 (71.6%) presented with ARDS. The factors found to be independently associated with mortality were IMV (p = 0.002), hypoalbuminemia (p = 0.013), and CD4 count < 200 cells/mm3 (p = 0.002). CONCLUSIONS: A high early mortality rate was observed among TB/HIV coinfected ICU patients. The factors predictive of mortality in this population were IMV, hypoalbuminemia, and severe immunosuppression.

Predictors of mortality among intensive care unit patients coinfected with tuberculosis and HIV / Preditores de mortalidade em pacientes da unidade de terapia intensiva coinfectados por tuberculose e HIV

ABSTRACT Objective: To identify factors predictive of mortality in patients admitted to the ICU with tuberculosis (TB)/HIV coinfection in the Manaus, Amazon Region. Methods: This was a retrospective cohort study of TB/HIV coinfected patients over 18 years of age who were admitted to an ICU in the city of Manaus, Brazil, between January of 2011 and December of 2014. Sociodemographic, clinical, and laboratory variables were assessed. To identify factors predictive of mortality, we employed a Cox proportional hazards model. Results: During the study period, 120 patients with TB/HIV coinfection were admitted to the ICU. The mean age was 37.0 ± 11.7 years. Of the 120 patients evaluated, 94 (78.3%) died and 62 (66.0%) of those deaths having occurred within the first week after admission. Data on invasive mechanical ventilation (IMV) and ARDS were available for 86 and 67 patients, respectively Of those 86, 75 (87.2%) underwent IMV, and, of those 67, 48 (71.6%) presented with ARDS. The factors found to be independently associated with mortality were IMV (p = 0.002), hypoalbuminemia (p = 0.013), and CD4 count < 200 cells/mm3 (p = 0.002). Conclusions: A high early mortality rate was observed among TB/HIV coinfected ICU patients. The factors predictive of mortality in this population were IMV, hypoalbuminemia, and severe immunosuppression.

RESUMO Objetivo: Identificar fatores preditores de mortalidade em pacientes da UTI coinfectados por tuberculose (TB)/HIV em Manaus (AM). Métodos: Estudo retrospectivo de coorte com pacientes coinfectados por TB/HIV, com mais de 18 anos de idade e admitidos na UTI entre janeiro de 2011 e dezembro de 2014. Foram avaliadas variáveis sociodemográficas, clínicas e laboratoriais. Para identificar fatores preditores de mortalidade, foi empregado um modelo de riscos proporcionais de Cox. Resultados: Durante o período estudado, 120 pacientes com coinfecção por TB/HIV foram admitidos na UTI. A média de idade foi de 37,0 ± 11,7 anos. Dos 120 pacientes avaliados, 94 (78,3%) morreram; dos 94 óbitos, 62 (66,0%) ocorreram na primeira semana após a admissão. Havia dados sobre ventilação mecânica invasiva (VMI) e SARA referentes a 86 e 67 pacientes, respectivamente. Dos 86, 75 (87,2%) foram submetidos a VMI, e, dos 67, 48 (71,6%) apresentaram SARA. Os fatores que se relacionaram independentemente com a mortalidade foram VMI (p = 0,002), hipoalbuminemia (p = 0,013) e contagem de CD4 < 200 células/mm3 (p = 0,002). Conclusões: Elevada mortalidade precoce foi observada em pacientes com coinfecção por TB/HIV admitidos na UTI. Os fatores preditores de mortalidade nessa população foram VMI, hipoalbuminemia e imunodepressão grave.