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.

Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial.

Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain. Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin. Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBACFU0-14) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13. Measurements and Main Results: Sixty participants enrolled. Median EBACFU0-14 counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-0.37), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log10 h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events. Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens. Clinical trial registered with www.clinicaltrials.gov (NCT03174184).

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.

The Pharmacokinetics of Crushed Levetiracetam Tablets Administered to Neonates.

BACKGROUND: Intravenous phenobarbital remains the first-line therapy in the management of neonatal seizures. Shortages of intravenous phenobarbital in South Africa necessitated the addition of oral levetiracetam as part of management of neonatal seizures. OBJECTIVE: We evaluated the pharmacokinetics of crushed immediate-release levetiracetam tablets administered to neonates to terminate seizures. METHODS: A prospective, observational study of neonates admitted with seizures to Tygerberg Hospital. Participants received crushed levetiracetam (diluted in saline) given orally or via naso-/orogastric tube. At steady-state, pharmacokinetic sampling was performed at pre-dose, 1.5, 2.5 and 4 h post-dose. Maximum concentration (Cmax), time to Cmax (Tmax), trough concentrations (Ctrough) and area under the concentration-time curve (AUC0-12) were calculated using non-compartmental analysis. Seizure termination and safety profiles were documented. RESULTS: Nineteen participants were grouped into three dosing ranges: (i) 5-15 mg/kg/12-hourly, (ii) 15-25 mg/kg/12-hourly and (iii) 25-35 mg/kg/12-hourly. Range 1 demonstrated AUC0-12 167.0 ± 45.6 h*µg/mL, Cmax 19.19 ± 4.12 µg/mL and Ctrough 9.99 ± 3.86 µg/mL. Range 2, AUC0-12 316.5 ± 108.4 h*µg/mL, Cmax 35.12 ± 10.54 µg/mL and Ctrough 19.25 ± 8.48 µg/mL. Range 3, AUC0-12 290.9 (range 176.14-405.59) h*µg/mL, Cmax 36.11 (range 27.58-44.64) µg/mL and Ctrough 13.03 (2.98-23.07) µg/mL. Seizures terminated in 17/19 (90%) neonates by day 3 and 19/19 (100%) by day 4 post-levetiracetam initiation. CONCLUSION: Crushed levetiracetam has comparable pharmacokinetics to historical data. No pharmacokinetic differences were observed between oral vs. naso-/orogastric administration. Crushed levetiracetam tablets can be considered for neonates in low-resource settings where intravenous and syrup access is limited. LAY SUMMARY: Intravenous preparations of antiepileptic medications are used in the management of neonatal seizures. Various established standard of care intravenous antiepileptic medicines are unavailable nationally and internationally due to reasons outside our control. This stock shortage included intravenous phenobarbitone which is the first-line treatment for paediatric seizures. Due to phenobarbital shortage, levetiracetam has been identified by the neonatologists at Tygerberg Hospital, Cape Town, South Africa, as a suitable treatment option due to its efficacy and safety profile. However, intravenous levetiracetam and oral syrup is not registered in South Africa. Levetiracetam tablets are being crushed, dissolved and administered to neonates. There are no data available on the absorption of crushed levetiracetam tablets administered to neonates via a nasogastric tube. This study characterized the pharmacokinetic profile of crushed levetiracetam administered to neonates. We selected neonates receiving levetiracetam from the neonatal wards at Tygerberg hospital and drew blood to analyse the levetiracetam concentrations at 4 different time points. We found that the overall exposure of crushed levetiracetam tablets were comparable to the exposures achieved in historical data of the unaltered formulations. We concluded that crushed levetiracetam tablets can be considered for neonates in low resource settings where intravenous and syrup access is limited.

The pharmacokinetics of para-aminosalicylic acid and its relationship to efficacy and intolerance.

Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.

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

BACKGROUND: South Africa has one of the highest tuberculosis incidence rates. Biologic disease-modifying anti-rheumatic 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.

Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens.

PURPOSE: Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens. METHODS: To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER. RESULTS: The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for ≥ 98% of the dosing interval in all the evaluated PASER regimens. CONCLUSION: The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.

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 <1%. 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. TRIAL REGISTRATION NUMBER: NCT04807504; clinicaltrials.gov.

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.

Pharmacokinetics of Para-Aminosalicylic Acid and Its 2 Major Metabolites: A Potential Relationship to the Development of Gastrointestinal Intolerance.

Para-aminosalicylic acid (PAS), often the last drug remaining for treatment of drug-resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (Cmax ) and intolerance scores. A large interindividual variability was observed for the PAS Cmax (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide Cmax range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS Cmax and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.

Evaluation of the Effectiveness of Dose Individualization to Achieve Therapeutic Vancomycin Concentrations.

The glycopeptide antibiotic vancomycin is used for treatment of methicillin-resistant Gram-positive cocci. Adequate vancomycin plasma concentrations are related to bacterial cure. However, inter- and intrapatient variability make it difficult to achieve therapeutic vancomycin concentrations. The primary objective of this study was to determine the effectiveness of using computerized therapeutic drug monitoring (TDM) to assist in achieving therapeutic vancomycin concentrations at a tertiary hospital in South Africa. This was a 2-period study consisting of a retrospective 1-month observational period followed by a prospective 1-month period in which computerized TDM was implemented as an intervention to assist with vancomycin dose individualization. During the prospective period, all vancomycin TDM results were followed by dosage individualization using computerized TDM. The retrospective period included 77 patients with 292 vancomycin concentrations: 69% (53/77) adult and 31% (24/77) pediatric patients. The prospective period included 80 patients with 217 vancomycin concentrations measured: 69% (55/80) adult and 31% (25/80) pediatric patients. Fewer vancomycin TDM data were requested during the prospective period with a median (interquartile range) of 2 (1-3) samples per patient compared with 3 (1-5) samples per patient during the retrospective period. The odds ratio of achieving therapeutic trough concentrations was 3.63 (95%CI 1.81-7.3) in the prospective period when TDM-adjusted vancomycin dosing and appropriate TDM procedures were applied. The use of computerized TDM resulted in a higher frequency of therapeutic vancomycin concentrations in a middle-income setting. Trough vancomycin concentrations alone correlate poorly with the area under plasma concentration-time curve from 0 to 24 hours.