Incident tuberculosis disease in patients receiving biologic therapies in the Western Cape, South Africa from 2007 to 2018

CITATION: Du Toit, T., 2019. Incident tuberculosis disease in patients receiving biologic therapies in the Western Cape, South Africa from 2007 to 2018. BMC Infectious Diseases, 20:900, doi:10.1186/s12879-020-05624-0.The original publication is available at https://bmcinfectdis.biomedcentral.comBackground: South Africa has one of the highest tuberculosis incidence rates. Biologic disease-modifying antirheumatic drugs are associated with an increased risk of tuberculosis. The objective of this study was to describe the tuberculosis disease incidence rate among public sector patients receiving biologic therapies in the Western Cape Province. Methods: A retrospective, descriptive analysis was undertaken using routine health data collated by the Provincial Health Data Centre from January 2007 (first use of biologic therapy in the Western Cape) to September 2018. Results: We identified 609 patients treated with tumour necrosis factor-alpha (TNF-α) or non-TNF-α biologic therapies. Thirty-seven (37) patients developed tuberculosis after biologic therapy exposure, of whom the majority (78%) had an immune mediated inflammatory disease and the remainder (22%) a haematologic malignancy. The incidence rate of tuberculosis per 100,000 person-years was 2227 overall [95% confidence interval (CI): 1591, 3037]. Patients treated with TNF-α inhibitors and non-TNF-α inhibitors had estimated incidence rates of 2819 [95% CI: 1669, 4480] and 1825 [95% CI: 1131, 2797], respectively (p = 0.10). Conclusion: Patients exposed to both TNF-α and non-TNF-α biologic therapies may have a higher incidence of tuberculosis disease compared to the background risk of 681 cases per 100,000 per year in the Western Cape.https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-05624-0Publisher's versio

The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity

New and Repurposed Drugs for the Treatment of Active Tuberculosis: An Update for Clinicians

Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6 months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK), emergence of drug resistance, presence of comorbidities, and adverse drug reactions complicate TB therapy and drive the need for new drugs and/or regimens. Hence, new compounds are being developed, available drugs are repurposed, and the dosing of existing drugs is optimized, resulting in the largest drug development portfolio in TB history. This review highlights a selection of clinically available drug candidates that could be part of future TB regimens, including bedaquiline, delamanid, pretomanid, linezolid, clofazimine, optimized (high dose) rifampicin, rifapentine, and para-aminosalicylic acid. The review covers drug development history, preclinical data, PK, and current clinical development

Population pharmacokinetic and safety analysis of ropivacaine used for erector spinae plane blocks

Introduction Erector spinae plane blocks have become popular for thoracic surgery. Despite a theoretically favorable safety profile, intercostal spread occurs and systemic toxicity is possible. Pharmacokinetic data are needed to guide safe dosing. Methods Fifteen patients undergoing thoracic surgery received continuous erector spinae plane blocks with ropivacaine 150 mg followed by subsequent boluses of 40 mg every 6 hours and infusion of 2 mg/hour. Arterial blood samples were obtained over 12 hours and analyzed using non-linear mixed effects modeling, which allowed for conducting simulations of clinically relevant dosing scenarios. The primary outcome was the Cmax of ropivacaine in erector spinae plane blocks. Results The mean age was 66 years, mean weight was 77.5 kg, and mean ideal body weight was 60 kg. The mean Cmax was 2.5 ±1.1 mg/L, which occurred at a median time of 10 (7–47) min after initial injection. Five patients developed potentially toxic ropivacaine levels but did not experience neurological symptoms. Another patient reported transient neurological toxicity symptoms. Our data suggested that using a maximum ropivacaine dose of 2.5 mg/kg based on ideal body weight would have prevented all toxicity events. Simulation predicted that reducing the initial dose to 75 mg with the same subsequent intermittent bolus dosing would decrease the risk of toxic levels to \u3c1%. Conclusion Local anesthetic systemic toxicity can occur with erector spinae plane blocks and administration of large, fixed doses of ropivacaine should be avoided, especially in patients with low ideal body weights. Weight-based ropivacaine dosing could reduce toxicity risk

Drug concentration at the site of disease in children with pulmonary tuberculosis.

BackgroundCurrent TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB.ObjectivesTo determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB.MethodsWe quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions.ResultsIsoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions.ConclusionsDespite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid

Drug concentration at the site of disease in children with pulmonary tuberculosis

Background Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB. Objectives To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB. Methods We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions. Results Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions. Conclusions Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid