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BackgroundSuboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.MethodsWe systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24andCmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially 0–24for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide.N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants ofCmaxwere generally similar to those for AUC0–24.ConclusionsThis study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) remain limited, and para-aminosalicylic acid (PAS) is still a relevant component of treatment regimens. Prevention of resistance to companion drugs by PAS is dose related, and at higher concentrations, PAS may exhibit significant bactericidal activity in addition to its bacteriostatic properties. The optimal dosing of PAS in children is uncertain, specifically for delayed-release granule preparations, which are the most used. A population pharmacokinetic model was developed describing PAS pharmacokinetics in children receiving routine RR-TB treatment. Model-based simulations evaluated current World Health Organization (WHO) weight-band doses against the adult pharmacokinetic target of 50 to 100 mg/liter for peak concentrations. Of 27 children included, the median (range) age and weight were 3.87 (0.58 to 13.7) years and 13.3 (7.15 to 30.5) kg, respectively; 4 (14.8%) were HIV positive. PAS followed one-compartment kinetics with first-order elimination and transit compartment absorption. The typical clearance in a 13-kg child was 9.79 liters/h. Increased PAS clearance was observed in both pharmacokinetic profiles from the only patient receiving efavirenz. No effect of renal function, sex, ethnicity, nutritional status, HIV status, antiretrovirals (lamivudine, abacavir, and lopinavir-ritonavir), or RR-TB drugs was detected. In simulations, target concentrations were achieved only using the higher WHO dose range of 300 mg/kg once daily. A transit compartment adequately describes absorption for the slow-release PAS formulation. Children should be dosed at the higher range of current WHO-recommended PAS doses and in a once-daily dose to optimize treatment.

Mycobacterium tuberculosis culture from gastric lavage from apparently healthy children following tuberculin skin test conversion, despite normal chest radiography (CR), is well known but is a contentious subject. A consensus statement regarding classification of childhood tuberculosis excluded this condition, stating that more data were needed. To assist in this discussion, we reviewed early publications that reported the occurrence of this phenomenon and early anatomical pathology studies that described changes that occur in children following tuberculosis infection. Pathology studies describe frequent cavitation in primary foci in children from whom positive M. tuberculosis cultures might easily arise. These foci were very small in some children who might have normal CR. Positive cultures might also arise from ulcerated mediastinal lymph nodes that are invisible on CR. Young children with recent infection very likely have active primary pulmonary tuberculosis.

Item does not contain fulltext Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination.

BACKGROUND: High-dose isoniazid (INHH) (15–20 mg/kg/day) could be administered to overcome low-level INH resistance, but pharmacokinetic data are sparse.METHODS: This observational study included South African children (H as preventive therapy, or treatment for multidrug-resistant TB (MDR-TB) exposure or disease. Pharmacokinetic sampling was performed after an INH dose of 20 mg/kg. Non-compartmental analysis and multivariable regression models were used to evaluate associations of key covariates with area under the curve (AUC0–24) and maximum concentration (Cmax). AUC and Cmax values were compared against proposed adult targets.RESULTS: Seventy-seven children were included, with median age of 3.7 years; 51 (66%) had MDR-TB disease and 26 (34%) had MDR-TB exposure. Five were HIV-positive, of whom four were ≥5 years old. The median AUC0–24 was 19.46 µgh/mL (IQR 10.76–50.06) and Cmax was 5.14 µg/mL (IQR 2.69–13.2). In multivariable analysis of children aged 0–24 (geometric mean ratio GMR 0.19, 95% CI 0.15–0.26; P < 0.001) and Cmax (GMR 0.20, 95% CI 0.15–0.26; P < 0.001).CONCLUSIONS: INH concentrations in children with MDR-TB disease were much lower than expected, but comparable to previous reports in children with MDR-TB exposure. Further studies should confirm these findings and explore possible causes.

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.

Tuberculous meningitis (TBM) remains a major cause of morbidity and mortality in children with tuberculosis (TB), yet there are currently no estimates of the global burden of pediatric TBM. Due to frequent non-specific clinical presentation and limited and inadequate diagnostic tests, children with TBM are often diagnosed late or die undiagnosed. Even when diagnosed and treated, 20% of children with TBM die. Of survivors, the majority have substantial neurological disability with significant negative impact on children and their families. Surveillance data on this devastating form of TB can help to quantify the contribution of TBM to the overall burden, morbidity and mortality of TB in children and the epidemiology of TB more broadly. Pediatric TBM usually occurs shortly after primary infection with Mycobacterium tuberculosis and reflects ongoing TB transmission to children. In this article we explain the public health importance of pediatric TBM, discuss the epidemiology within the context of overall TB control and health system functioning and the limitations of current surveillance strategies. We provide a clear rationale for the benefit of improved surveillance of pediatric TBM using a TB care cascade framework to support monitoring and evaluation of pediatric TB, and TB control more broadly. Considering the public health implications of a diagnosis of TBM in children, we provide recommendations to strengthen pediatric TBM surveillance and outline how improved surveillance can help us identify opportunities for prevention, earlier diagnosis and improved care to minimize the impact of TBM on children globally.

Anton Ghon is well known in the field of childhood tuberculosis, and the tuberculosis primary focus and complex are frequently called the Ghon focus and complex; this is largely the result of the wide publication of the English translation of his monograph “Der primäre Lungenherd bei der Tuberkulose der Kinder.” Ghon’s studies are frequently quoted, but precise details of his monograph are neglected, his results often misquoted, and his later publications virtually unknown. This review highlights aspects of Ghon’s anatomical pathology studies in children and adults not necessarily dying of tuberculosis but with signs of tuberculosis infection. Ghon found a single primary tuberculosis focus in approximately 80% of tuberculosis-infected children situated close to the pleura in two-thirds of cases. Cavitation of the focus was common, and lymphatic spread involved lymph nodes in the abdomen and neck in many children. Studies amongst adults and children frequently found the healed primary tuberculosis focus to be completely calcified without histological signs of tuberculosis activity; however, particularly in the presence of pulmonary tuberculosis, histological signs of tuberculosis activity were often found in the lymph nodes of the angulus venosus, despite apparent healing with extensive calcification. Both earlier studies and more recent investigations, with molecular biological tools, unavailable to Ghon and earlier researchers, have confirmed the presence of viable mycobacteria in apparently normal or healed thoracic nodes and also found molecular biological indications of viable mycobacteria in these nodes. As suggested by Ghon, lympho-haematogenous spread of tuberculosis may be more common than is usually appreciated.

The transmission of tuberculosis (TB) occurs mainly via inhalation of airborne droplet nuclei; however, the precise details of this process remain uncertain. We reviewed the literature from 1870 to 1940, when Mycobacterium tuberculosis was discovered and the concept of transmission emerged as a hallmark of the infectious disease. By 1940, laboratory experiments, animal studies and clinical observation had demonstrated that cough was central to TB transmission, and that guinea pigs close to patients with cough could be infected, mainly by patients coughing small droplets likely containing only 1-2 bacilli. A minority of pulmonary TB patients, usually during the early stages of the disease, with thin watery sputum, more successfully coughed small infectious droplets than patients with heavily smear-positive tenacious sputum who were often too ill and too weak to cough vigorously. There was ongoing debate regarding the possible importance of desiccated sputum particles found in surface dust. Investigation of TB transmission has a history of more than 130 years.

The mutant prevention concentration (MPC) is a well-known concept in the chemotherapy of many bacterial infections, but is seldom considered in relation to tuberculosis (TB) treatment, as the required concentrations are generally viewed as unachievable without undue toxicity. Early studies revealed single mutations conferring high MICs of first- and second-line anti-TB agents; however, the growing application of genomics and quantitative drug susceptibility testing in TB suggests a wide range of MICs often determined by specific mutations and strain type. In paediatric TB, pharmacokinetic studies indicate that despite increasing dose recommendations, a proportion of children still do not achieve adult-derived targets. When considering the next stage in anti-TB drug dosing and the introduction of novel therapies for children, we suggest consideration of MPC and its incorporation into pharmacokinetic studies to more accurately determine appropriate concentration targets in children, to restrict the growth of resistant mutants and better manage drug-resistant TB.

Contains fulltext : 229215.pdf (Publisher’s version ) (Closed access) 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.

Item does not contain fulltext The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of >/= 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2 mug/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of >/= 8 microg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax >/= 22 mug/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC6) >/= 70 mug.h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.

There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (C max ) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 μg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 μg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC 0–8 ) were 12.1, 24.7, 239.4, and 5.1 μg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed in C max (geometric mean ratio [GMR] , 2.55; 95% confidence interval [CI], 1.47 to 4.41; P = 0.001) and AUC 0–8 (GMR, 2.52; 95% CI, 1.34 to 4.73; P = 0.005). HIV status was associated with lower pyrazinamide C max (GMR, 0.85; 95% CI, 0.75 to 0.96; P = 0.013) and AUC 0–8 (GMR, 0.79; 95% CI, 0.69 to 0.90; P < 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.)

Tuberculosis is a global pandemic that threatens to overwhelm healthcare budgets in many developing countries. Despite the availability of adequate effective treatment, many patients default on treatment, experience adverse side effects from antibiotics or fail to respond rapidly and recover. Isoniazid, one of the most important first-line tuberculosis drugs, is acetylated in the liver to a variable degree in different individuals giving rise to fast, intermediate and slow acetylator phenotypes. We present the view that the acetylation status of individuals plays an important contributory role in the tuberculosis pandemic. It is important to study the acetylation alleles, and to understand isoniazid metabolism and the manner in which it could affect patient compliance, isoniazid-toxicity and the emergence of drug-resistant strains of mycobacteria.

Tuberculosis (TB) remains a global threat to children, as it often goes undiagnosed and leads to high morbidity and mortality. Active contact tracing leading to initiation of preventive therapy and early diagnosis with immediate effective treatment, whether it is drug-susceptible or drug-resistant TB, could reduce mortality and morbidity. In order to achieve this it is necessary to understand the currently available drugs, their role in treatment, their doses, and adverse effects. However, there is still limited pharmacokinetic data on antituberculosis drugs in children, few child-friendly formulations, and knowledge gaps regarding their pharmacodynamics. A discussion of the available antituberculosis drugs is presented, with a focus on their pharmacokinetics and pharmacodynamics, to provide reasoning for the currently recommended doses for children. More pharmacokinetic and pharmacodynamics studies, for both existing and novel drugs, are urgently needed to optimize dosing of antituberculosis drugs in children and for development of child-friendly formulations.

The fluoroquinolones are key components of current multidrug-resistant tuberculosis (MDR-TB) treatment regimens and are being evaluated in shortened treatment regimens as well as in the prevention of drug-resistant TB. The objective of this review was to identify existing evidence for the use of the fluoroquinolones ofloxacin, levofloxacin and moxifloxacin in the treatment of TB in children. Existing data from in vitro, animal and human studies consistently demonstrate the efficacy of the fluoroquinolones against Mycobacterium tuberculosis, with superiority of levofloxacin and moxifloxacin compared to ofloxacin. In vitro and murine studies demonstrated the potential of moxifloxacin to shorten drug-susceptible TB treatment, but in multiple randomized controlled trials shortened fluoroquinolone-containing regimens have not been non-inferior compared to standard therapy. Resistance occurs frequently via mutations in the gyrA gene, and emerges rapidly depending on the fluoroquinolone concentration, with newer more potent fluoroquinolones less likely to develop resistance. Emerging data from paediatric studies underlines the importance of fluoroquinolones in the treatment of MDR-TB in children. There is a paucity of pharmacokinetic data especially in children5 years of age and HIV-infected children; existing studies show substantially lower serum concentrations in children compared to adults at currently recommended doses, probably due to faster elimination. This has implications for optimizing paediatric treatment and for the development of resistance. Fluoroquinolone use has been restricted in children due to concerns about drug-induced arthropathy. The available data does not demonstrate any serious arthropathy or other severe toxicity in children. Although there is limited paediatric safety data for the prolonged treatment of MDR-TB, extended administration of fluoroquinolones in adults with MDR-TB does not show serious adverse effects and there is no evidence suggesting less tolerability of fluoroquinolones in children. Additional study of moxifloxacin and levofloxacin for TB treatment and prevention in children is an urgent priority.

New regimens to shorten tuberculosis treatment and manage patients with drug-resistant tuberculosis who are infected with HIV are urgently needed. Experimental and clinical evidence suggests that the new drugs bedaquiline (B) and pretomanid (Pa), combined with an existing drug, pyrazinamide (Z), and a repurposed drug, clofazimine (C), may assist treatment shortening of drug-susceptible and drug-resistant tuberculosis.To evaluate the 14-day bactericidal activity of C and Z in monotherapy and in combinations with Pa and B.Groups of 15 treatment-naive, sputum smear-positive patients with pulmonary tuberculosis were randomized to receive combinations of B with Z-C, Pa-Z, Pa-Z-C, and Pa-C, or C or Z alone, or standard combination treatment for 14 days. The primary endpoint was the mean daily fall in log10 Mycobacterium tuberculosis CFU per milliliter sputum estimated by joint nonlinear mixed-effects Bayesian regression modeling.Estimated activities were 0.167 (95% confidence interval [CI], 0.075-0.257) for B-Pa-Z, 0.151 (95% CI, 0.071-0.232) for standard treatment, 0.124 (95% CI, 0.035-0.214) for B-Z-C, 0.115 (95% CI, 0.039-0.189) for B-Pa-Z-C, and 0.076 (95% CI, 0.005-0.145) for B-Pa-C. Z alone had modest activity (0.036; 95% CI, -0.026 to 0.099). C had no activity alone (-0.017; 95% CI, -0.085 to 0.053) or in combinations. Treatments were well tolerated and safe.B-Pa-Z, including two novel agents without resistance in prevalent M. tuberculosis strains, is a potential new tuberculosis treatment regimen. C had no measurable activity in the first 14 days of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01691534).

Recent early bactericidal activity (EBA) studies of isoniazid-based antituberculosis therapies have shown a lower EBA over the first two treatment days than in earlier years. To quantify this trend and evaluate factors contributing to it, we extracted individual data from 18 studies with a total of 182 participants using isoniazid-containing therapies between 1992 and 2015 at a single site and laboratory in Cape Town, South Africa. We recalculated EBA as the daily fall in CFU per milliliter sputum up to day 2 of therapy (EBA 0–2 ) for individual patients and treatment groups and used mixed-effects linear models to investigate the correlation between pretreatment CFU, EBA 0–2 , and year of study. We found that mean pretreatment CFU and year of study accounted for 46% and 47%, respectively, of the variation in mean EBA 0–2 . Mean pretreatment CFU differed between the periods 1992 to 2001 and 2007 to 2015 by 0.92 log 10 CFU (95% confidence interval [CI], 0.57 to 1.28; P < 0.0001). On average, pretreatment CFU dropped by 0.053 log 10 CFU (95% CI, 0.029 to 0.076; P = 0.0004) and EBA 0–2 by 0.012 log 10 CFU (95% CI, 0.006 to 0.018; P = 0.001) per year. The EBA 0–2 of isoniazid-based antituberculosis therapy is strongly correlated with baseline mycobacterial load and shows a declining trend over the past 2 decades.

Unlike in pulmonary multidrug-resistant (MDR) tuberculosis, the clinical outcome of MDR tuberculous meningitis (TBM) in children, including extensively drug-resistant tuberculosis, is poor and management is challenging. We report the successful treatment of a case of extensively drug-resistant TBM in a 4-year-old girl, and we discuss implications for tuberculosis diagnosis and chemotherapy.

Summary Time to culture positivity (TTP) in liquid medium is now widely available as a measure of viable mycobacterial sputum load. TTP correlates well with and could replace colony-forming unit (CFU) counting in studies of antituberculosis drug effects. We investigated the influence of the pre-treatment mycobacterial sputum load on 4428 CFU measurements obtained within the first 14 days of treatment. Using a prediction model we show that pre-treatment CFU counts contribute 29% to the variation of on-treatment CFU counts and increase the precision of the prediction of on-treatment CFU from TTP by 12%. On the other hand, pre-treatment TTP contributed only 12% to the variation of on-treatment TTP and only added 2% to the prediction of TTP from CFU. We conclude pre-treatment measurements are covariates that can enhance the accuracy of statistical estimates of treatment effects, particularly when measured by CFU counts.

Time to liquid culture positivity (TTP) is a technically accessible and widely available measure of viable mycobacterial load in sputum samples. We describe the ability of TTP to predict colony forming unit counts of Mycobacterium tuberculosis from sputum samples collected before or during the first 14 days of antituberculosis therapy.

Rifampicin was discovered in 1965 and remains one of the most important drugs in tuberculosis treatment that is valued for its sterilizing activity and ability to shorten treatment. Antimicrobial activity of rifampicin was initially proved in vitro; subsequently numerous in vivo studies showed the bactericidal properties and dose-dependent effect of rifampicin. Rifampicin was first during the late 1960s to treat patients suffering from chronic drug-resistant pulmonary TB. Decades later, rifampicin continues to be studied with particular emphasis on whether higher doses could shorten the duration of treatment without increasing relapse or having adverse effects. Lesion-specific drug penetration and pharmacokinetics of rifampicin are improving our understanding of effective concentration while potentially refining drug regimen designs. Another prospective aspect of high-dose rifampicin is its potential use in treating discrepant mutation thereby eliminating the need for MDR treatment. To date, several clinical trials have shown the safety, efficacy, and tolerability of high-dose rifampicin. Currently, high-dose rifampicin has been used successfully in a routine clinical setting for the treatment of high-risk patients. However, the WHO and other relevant policy makers have not committed to implementing a controlled rollout thereof. This review describes the course that rifampicin has travelled to the present-day exploration of high-dose rifampicin treatment.

To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures.We used previously published data for 76 South African children with tuberculosis to describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid. Monte Carlo simulations were used to predict steady-state exposures in children following doses in fixed-dose combination tablets in accordance with the revised guidelines. Reference exposures were derived from an ethnically similar adult population with tuberculosis taking currently recommended doses.The final models included allometric scaling of clearance and volume of distribution using body weight. Maturation was included for clearance of isoniazid and clearance and absorption transit time of rifampicin. For a 2-year-old child weighing 12.5 kg, the estimated typical oral clearances of rifampicin and pyrazinamide were 8.15 and 1.08 L/h, respectively. Isoniazid typical oral clearance (adjusted for bioavailability) was predicted to be 4.44, 11.6 and 14.6 L/h for slow, intermediate and fast acetylators, respectively. Higher oral clearance values in intermediate and fast acetylators also resulted from 23% lower bioavailability compared with slow acetylators.Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing.

Introduction: Novel therapeutic agents are urgently needed to combat drug-resistant tuberculosis. Delamanid is a new 6-nitro-2,3-dihydroimidazo[2,1-b]oxazole developed from a new chemical group to which no resistance exists. Preclinical experience found delamanid efficacious with a good safety profile except for QT prolongation; in vitro no interaction, inhibitory nor stimulatory with human and animal liver microsomes or a range of CYP enzymes have been demonstrated; interactions with antiretroviral agents are unlikely but this must still be demonstrated in clinical trials. A dose-ranging early bactericidal activity study provided proof of concept, and a controlled trial over the first 8 weeks of multidrug-resistant tuberculosis treatment found accelerated sputum culture negativity. Delamanid is in ongoing clinical trials in children, adults and HIV-infected adults receiving antiretroviral treatment. Areas covered: Using keywords, such as imidazooxazole, nitroimidazoles, OPC-67683, delamanid and antituber...

Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log 10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant ( P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group ( P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.

Edith Lincoln (1899-1971), one of the most influential American pediatricians to study childhood tuberculosis, managed more than a thousand children from time of tuberculosis infection into adult life. She spoke with authority regarding the prognosis of childhood tuberculosis. Her observations of chemotherapy in children treated with isoniazid led directly to chemoprophylaxis, now of great importance in the management of the human immunodeficiency syndrome.

Summary Background Case fatality ratios in children with tuberculosis are poorly understood—particularly those among children with HIV and children not receiving tuberculosis treatment. We did a systematic review of published work to identify studies of population-representative samples of paediatric (ie, Methods We searched PubMed and Embase for reports published in English, French, Portuguese, or Spanish before Aug 12, 2016, that included terms related to tuberculosis, children, mortality, and population representativeness. We also reviewed our own files and reference lists of articles identified by this search. We screened titles and abstracts for inclusion, excluding studies in which outcomes were unknown for 10% or more of the children and publications detailing non-representative samples. We used random-effects meta-analysis to produce pooled estimates of case fatality ratios from the included studies, which we divided into three eras: the pre-treatment era (ie, studies before 1946), the middle era (1946–80), and the recent era (after 1980). We stratified our analyses by whether or not children received tuberculosis treatment, age (0–4 years, 5–14 years), and HIV status. Findings We identified 31 papers comprising 35 datasets representing 82 436 children with tuberculosis disease, of whom 9274 died. Among children with tuberculosis included in studies in the pre-treatment era, the pooled case fatality ratio was 21·9% (95% CI 18·1–26·4) overall. The pooled case fatality ratio was significantly higher in children aged 0–4 years (43·6%, 95% CI 36·8–50·6) than in those aged 5–14 years (14·9%, 11·5–19·1). In studies in the recent era, when most children had tuberculosis treatment, the pooled case fatality ratio was 0·9% (95% CI 0·5–1·6). US surveillance data suggest that the case fatality ratio is substantially higher in children with HIV receiving treatment for tuberculosis (especially without antiretroviral therapy) than in those without HIV. Interpretation Without adequate treatment, children with tuberculosis, especially those younger than 5 years, are at high risk of death. Children with HIV have an increased mortality risk, even when receiving tuberculosis treatment. Funding US National Institutes of Health, Janssen Global Public Health.

Tuberculous meningitis causes substantial mortality and morbidity in children and adults. More research is urgently needed to better understand the pathogenesis of disease and to improve its clinical management and outcome. A major stumbling block is the absence of standardised diagnostic criteria. The different case definitions used in various studies makes comparison of research findings difficult, prevents the best use of existing data, and limits the management of disease. To address this problem, a 3-day tuberculous meningitis workshop took place in Cape Town, South Africa, and was attended by 41 international participants experienced in the research or management of tuberculous meningitis. During the meeting, diagnostic criteria were assessed and discussed, after which a writing committee was appointed to finalise a consensus case definition for tuberculous meningitis for use in future clinical research. We present the consensus case definition together with the rationale behind the recommendations. This case definition is applicable irrespective of the patient's age, HIV infection status, or the resources available in the research setting. Consistent use of the proposed case definition will aid comparison of studies, improve scientific communication, and ultimately improve care.

Summary Background New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. Methods In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. Findings The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. Interpretation PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. Funding The Global Alliance for TB Drug Development (TB Alliance).

The association of childhood tuberculosis (TB) and malnutrition is known, but treatment response, the influence of the acute-phase response (APR) and concomitant HIV infection are not well documented.To evaluate the nutritional response and APR in HIV-infected and uninfected children hospitalised for the treatment of TB and receiving standard anti-tuberculosis chemotherapy.During a study of the pharmacokinetics of standard anti-tuberculosis agents, anthropometric parameters were measured and blood concentrations of nutrients and C-reactive protein (CRP) determined at 1 and 4 months after initiation of chemotherapy.24 HIV-infected and 34 HIV-uninfected children were studied. On enrollment, 31.6% of HIV-infected and 2.9% of HIV-uninfected children were underweight, and 31.6% and 14.7%, respectively, were stunted. Mean values of weight, height/length, head circumference and mid-upper-arm circumference on enrollment and at 4-month assessment in HIV-infected and uninfected children did not differ. Mean triceps skinfold (TSF) (8.17 and 9.73 cm) and subscapular skinfold (SSF) thicknesses (5.75 and 7.5 cm) on enrollment differed significantly (P = 0.03 and P = 0.003); by 4 months, TSF had declined to 5.97 cm (P0.001) and 8.87 cm (P = 0.05), respectively, and SSF to 5.57 cm (P = 0.79) and 6.73 cm (P = 0.04); the arm muscle area (AMA) was low in a majority of children on enrollment and remained so at the second assessment. CRP was raised in 66.6% and 53.3% of HIV-infected and -uninfected children on enrollment, but at 4-month assessment was raised in 63.2% and 15.2%, respectively. Other micronutrient and haematological findings probably reflect an APR, but no children had sub-normal zinc or magnesium values; most selenium and vitamin C and E values were normal. An elevated platelet count (420 × 10(9)/L) was significantly more common in HIV-uninfected children, and was still raised in 39% at 4 months.A majority of HIV-infected and uninfected children had an APR but it had resolved by 4 months in most HIV-uninfected children. In both groups, low and declining skinfolds and a persistently low AMA indicate a persistent disturbance of fat and protein metabolism, despite successful chemotherapy.

Tuberculosis (TB) in children has conventionally been classified as pulmonary TB (PTB) and extrapulmonary TB (EPTB) disease, including disseminated TB (TB meningitis and miliary disease). There is no existing approach that comprehensively characterizes the spectrum and severity of pediatric TB. This limits accurate classification of patients and comparison across cohorts.To develop a classification of pediatric TB that reflects the spectrum and severity of clinical disease better than currently available approaches.We propose a framework for the standard classification of TB disease severity in children. From a literature search, the following sources of information were used: clinical data, bacteriologic, histopathologic, and imaging data (including information from chest radiography, computerized tomography, and bronchoscopy). Each individual disease entity was systematically considered. Based on the extent and the presence of complications, each entity was then classified as "severe" or "nonsevere." As an initial application, we compared the proposed classification with the convention (PTB, EPTB) in a cohort of HIV-infected and -uninfected infants with culture-confirmed TB. Agreement between the 2 systems was poor.The proposed comprehensive disease classification system may more accurately reflect the clinical TB disease spectrum in children, is relevant to clinical management, and may be valuable to inform research on diagnostic tools and TB treatment strategies in children. Prospective studies are required to evaluate this approach in representative pediatric populations, correlating TB disease severity with diagnostic yield, treatment response, and application in existing and novel treatment strategies.

Pyrazinamide (PZA) is an essential sterilizing drug and with rifampicin enables six-month short-course antituberculosis chemotherapy. Despite routine use for nearly forty years uncertainty remains regarding the most appropriate PZA dosage for children. In view of this uncertainty literature relating to the efficacy and pharmacokinetics of PZA in children treated for tuberculosis and in adult volunteers and patients was reviewed. Making use of the PZA maximum concentration (C(max)) following various PZA dosages in different groups straight line regression of concentration on dosage was fitted through the origin by least squares and weighted for the numbers of subjects. The fitted line offers an approximation of the likely PZA C(max) that would result from a particular dosage. The slopes of C(max)/dosage of the fitted lines are 1.32 (SE 0.099) for paediatric patients, 1.36 (SE 0.051) for adult volunteers and 1.35 (SE 0.037) for adult patients; there is little difference between the C(max) concentrations achieved in children and adults, whether patients or healthy volunteers, following various mg/kg body weight dosages, suggesting that children and adults receiving the same mg/kg body weight PZA dosage will reach a similar C(max). Children can receive the same mg/kg body weight PZA dosage as adults.

SETTING Tygerberg Children's Hospital (TCH) and Brooklyn Chest Hospital (BCH), South Africa. OBJECTIVES To describe paediatric cases of rifampicin (RMP) monoresistant tuberculosis (RMR-TB) disease. DESIGN Records of children with culture-confirmed RMR-TB between 1 March 2003 and 28 February 2009 were identified from a prospectively recorded database of drug-resistant TB at TCH and BCH. Mutation analysis was performed on available specimens. RESULTS Eighteen children with a median age of 6.9 years (range 2 months-12.8 years) were identified. Nine (50%) were human immunodeficiency virus (HIV) infected and four (22%) were HIV-exposed but non-infected. Eleven (61%) had had previous TB treatment or prophylaxis. Nine children (50%) had cavitary disease and five children (22%) had extra-pulmonary disease. Twelve (67%) had adult TB source cases, including five (42%) adults with known RMR-TB. Primary transmission occurred among 11 children (61%) and acquisition of RMR-TB was possible in seven (39%) with prior RMP exposure. Median delay to specific RMR-TB treatment was 70 days (range 23-188). One child died from RMR-TB meningitis. Gene mutations consistent with RMR-TB were confirmed in five available samples. CONCLUSION RMR-TB disease is increasingly encountered, particularly among HIV-infected and HIV-exposed non-infected children. Delay in commencing appropriate treatment for RMR-TB and high rates of cavitary disease could be a source of RMR-TB transmission.

BACKGROUND: Few studies have described children with spinal multidrug-resistant tuberculosis (MDR-TB). Treatment involves surgery and medical care with long courses of drug therapy. METHODS: Hospital and laboratory records at Brooklyn Chest and Tygerberg Children's Hospitals, Cape Town, South Africa, were analysed (January 2004 until December 2010) searching for children treated for MDR spinal TB. RESULTS: Of the 11 children identified, 4 were excluded. Of the 7 remaining, 5 were boys; median age: 8 years, median delay to treatment initiation: 36 weeks. Among them one child died, five have completed treatment and one is near the end of therapy. Medications were well-tolerated and although two of the surviving children have spinal deformity, none have significant neurological deficit. CONCLUSIONS: The diagnosis of spinal MDR-TB is often delayed in children, frequently leading to advanced disease and severe vertebral damage. Children tolerate therapy well and, once identified, it is a condition that can be treated successfully.

Background. Multidrug-resistant tuberculosis in children is poorly described. We document the clinical presentation, time to treatment initiation, and outcomes in a cohort of 111 children with culture-confirmed multidrug-resistant tuberculosis. Methods. All children < 15 years of age with a diagnosis of culture-confirmed MDR-tuberculosis were included in this retrospective cohort study from 1 January 2003 to 31 December 2008, with follow-up documented until 31 May 2011. We identified children from Brooklyn Hospital for Chest Diseases and Tygerberg Children's Hospital, Western Cape Province, South Africa. Treatment outcomes were defined as 2-month sputum-culture conversion, treatment episode outcome, and survival. Results. A total of 111 children (median age, 50 months) were included. The diagnosis was delayed in children who had no identified MDR-tuberculosis index case (median delay, 123 vs 58 days; P < .001). Sixty-two percent of patients (53 of 85) were sputum-smear positive, and 43% of patients (43 of 100) were human immunodeficiency virus (HIV) infected. Overall, 82% had favorable treatment outcomes; total mortality was 12%. Malnutrition was associated with failure to culture-convert at 2 months (odds ratio [OR], 4.49 [95% confidence interval {CI}, 1.32-15.2]; P = .02) and death (OR, 15.0 [95% CI, 1.17-192.5]; P = .04) in multivariate analysis. HIV coinfection (OR, 24.7 [95% CI, 1.79-341.1]; P = .02) and the presence of extrapulmonary tuberculosis (OR, 37.8 [95% CI, 2.78-513.4]; P = .006) predicted death. Conclusions. Despite advanced disease at presentation and a high prevalence of human immunodeficiency virus coinfection, children with MDR-tuberculosis can be treated successfully, using individualized treatment under routine conditions.

Ethionamide (ETH), a second-line antituberculosis drug, is frequently used in treating childhood tuberculosis. Data supporting ETH dose recommendations in children are limited. The aim of this study was to determine the pharmacokinetic parameters for ETH in children on antituberculosis treatment including ETH. ETH serum levels were prospectively assessed in 31 children in 3 age groups (0 to 2 years, 2 to 6 years, and 6 to 12 years). Within each age group, half received rifampin (RMP). Following an oral dose of ETH (15 to 20 mg/kg of body weight), blood samples were collected at 0, 1, 2, 3, 4, and 6 h following 1 and 4 months of ETH therapy. The maximum serum concentration ( C max ), time to C max ( T max ), and area under the time-concentration curve from 0 to 6 h (AUC 0–6 ) were calculated. Younger children were exposed to lower ETH concentrations than older children at the same mg/kg body weight dose. Age correlated significantly with the AUC after both 1 month ( r = 0.50, P = 0.001) and 4 months ( r = 0.63, P = 0.001) of therapy. There was no difference in the AUC or C max between children receiving concomitant treatment with RMP and those who did not. Time on treatment did not influence the pharmacokinetic parameters of ETH following 1 and 4 months of therapy. HIV infection was associated with lower ETH exposure. In conclusion, ETH at an oral dose of 15 to 20 mg/kg results in sufficient serum concentrations compared to current adult recommended levels in the majority of children across all age groups. ETH levels were influenced by young age and HIV status but were not affected by concomitant RMP treatment and duration of therapy.

Diagnosis of pulmonary tuberculosis (PTB) in children is challenging and radiographs are often normal or non-specific. Access to the chest using ultrasound is difficult, but access to the abdomen is simple and carries no radiation burden. Diagnosis of PTB using abdominal lymphadenopathy as a surrogate for mediastinal lymphadenopathy may present a simple and accurate additional diagnostic technique that is of value in developing countries. We determined the prevalence of abdominal lymphadenopathy in paediatric patients with confirmed TB presenting with respiratory symptoms. Chest radiographs and abdominal ultrasounds of 47 children with confirmed TB and respiratory symptoms were reviewed. The prevalence of abdominal TB was determined and comparisons made between thoracic and abdominal lymphadenopathy to determine the relative value of ultrasound. On ultrasound, the prevalence of abdominal lymphadenopathy was 19% and solid organ involvement was found in 23% of patients. Some 70% of children had thoracic lymphadenopathy on chest radiography, with 89% of patients having evidence of PTB. If chest radiography were to be considered the radiological reference standard, abdominal ultrasonography had a sensitivity of 18% (95% CI 7.0–35.5%) with a specificity of 79% (95% CI 49.2–95.1%) for thoracic lymphadenopathy. Ultrasound and chest radiography in combination detected a total of 36 patients with lymphadenopathy, with a 6% improvement in the rate of lymphadenopathy detection; however, this was not statistically significant. The prevalence of abdominal TB of 23% is noteworthy. We suggest that abdominal ultrasound has a definitive adjunctive role in investigating children with suspected TB.

Background Delamanid (OPC-67683) is a novel mycolic acid biosynthesis inhibitor active against Mycobacterium tuberculosis at a low minimum inhibitory concentration. Methods Forty-eight patients with smear-positive tuberculosis (63% male; 54.7 ± 9.9 kg; 30.7 ± 10.8 years) were randomly assigned to receive delamanid 100, 200, 300 or 400 mg daily for 14 days. Colony forming units (cfu) of M. tuberculosis were counted on agar plates from overnight sputum collections to calculate early bactericidal activity (EBA), defined as fall in log(10) cfu/ml sputum/day. Results The EBA of delamanid was monophasic and not significantly different between dosages; however, more patients receiving 200 mg (70%) and 300 mg (80%) experienced a response of ≥0.9 log(10) cfu/ml sputum decline over 14 days than those receiving 100 mg (45%) and 400 mg (27%). The average EBA of all dosages combined (0.040 ± 0.056 log(10) cfu/ml sputum/day) was significant from day 2 onward. Delamanid exposure was less than dosage-proportional, reaching a plateau at 300 mg, likely due to dose-limited absorption. Moderate but significant correlation was found between C(max) and EBA, indicating exposure dependence. Delamanid was well tolerated without significant toxicity. Conclusions Delamanid at all dosages was safe, well tolerated and demonstrated significant exposure-dependent EBA over 14 days, supporting further investigation of its pharmacokinetics and anti-tuberculosis activity.

Pyrazinamide plasma concentrations were determined in 34 children (median age, 3.32 years) 1 month after commencing antituberculosis treatment. The median (interquartile range) peak concentration was 30.7 (25.5, 35.0) mg/L after a median dose of 23 mg/kg. Peak concentrations20 mg/L were found in 5 children (15%) and such low concentrations were particularly likely after doses20 mg/kg.

Drug resistance in children with tuberculosis is usually primary (transmitted); however, resistance acquisition during treatment is possi- ble. We describe a child with tuberculosis who acquired drug resistance while receiving directly observed but inadequate first-line therapy and the programmatic and clinical factors that may have contributed to resistance acquisition.

Anna Ridge,1* Patti Whyte,2 Malgosia Grzemska,3 Peter Donald4 and Suzanne Hill1 1Medicine Access and Rational Use, Department of Essential Medicines and Pharmaceutical Policies, World Health Organization, Geneva, Switzerland 21/10 Joan Avenue, Dromana, Victoria, Australia 3936 3Tuberculosis, Operations and Coordination, Stop TB Department, World Health Organization, Geneva, Switzerland 4Department of Paediatrics and Child Health and Division of Molecular Biology and Human Genetics and the MRC Centre for Molecular and Cellular Biology, DST/NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, University of Stellenbosch and Tygerberg Children’s Hospital, Stellenbosch, South Africa

Literature dealing with antituberculosis chemotherapy of tuberculous meningitis (TBM) in adults and children is reviewed and recommendations made for the chemotherapy of TBM. Publications relating to the chemotherapy of TBM were reviewed which contribute to understanding the efficacy of different drugs and regimens in TBM treatment. The established classification of disease severity into stages I (no neurological signs and fully conscious), II (patients conscious but with neurological signs) and III (comatose or stuporous or with severe pareses) was used to compare regimens of isoniazid (INH), para-amino salicylic acid and streptomycin (INH regimens) used up to approximately 1970 with those using INH and rifampicin (RMP), supported by pyrazinamide and ethambutol or streptomycin (RMP regimens). Mortality in studies at all disease stages in adults or adults and children, with the children not distinguished, following INH regimens (12.4%, 25.2% and 55% at stages I, II and III respectively) did not differ significantly from that following introduction of RMP regimens (9.7%, 22.2% and 56% at stages I, II and III respectively), In studies of children only, mortality fell significantly following the introduction of RMP to 0%, 5.9% and 28.2% in children at stage I, II and III having been 10.2%, 22.3% and 49.4% respectively with INH regimens (P = 0.006). Following RMP regimens of 6 months duration, only 2 (1%) relapses occurred amongst 197 patients, after RMP regimens of 9-24 months only 1 (0.16%) relapse was recorded amongst 632 patients. Where INH resistance rates are4% a directly observed INH, RMP, pyrazinamide and ethambutol for 2-months followed by INH and RMP for 4 months is recommended. If directly observed therapy cannot be practiced treatment duration should be extended to at least 9 months; if the risk of INH resistance or multidrug resistance is higher, the use of ethionamide and a fluoroquinolone and possibly cycloserine is recommended and pyrazinamide should be continued for full treatment duration. The penetration of RMP, ethambutol and streptomycin into cerebrospinal fluid is poor; higher dosages of RMP should be considered.

Evaluation of early bactericidal activity (EBA) by the determination of a fall in viable colony-forming units (CFU) of Mycobacterium tuberculosis in sputum is a first step in the clinical study of new antituberculosis agents. The time to detection (TTD) of growth in liquid media is more sensitive and could substitute for CFU counting on solid media. Overnight sputum samples collected during the evaluation of the novel agent TMC207 in comparison to isoniazid and rifampicin were studied. For the determination of CFU, we incubated 10-fold dilutions of homogenized sputum on selective 7H10 agar. The TTD was measured by incubating decontaminated sputum in the BACTEC MGIT 960 system. The fall in bacillary load over 7 days determined by CFU counting closely matched the prolongation of the TTD in the BACTEC MGIT 960 system. The CFU counts correlated significantly with the TTD. While the ranking of agents and different dosages of TMC207 was similar, the highest dose of TMC207 showed markedly better activity when measured by the TTD than CFU counting when compared to the activity of isoniazid. Automated TTD could augment, or, in future, replace, CFU counting to determine sputum bacillary load in EBA clinical trials pending a more formal evaluation of the correlation of the measurements.