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Introduction\ud \ud Multidrug-resistant tuberculosis (MDR-TB) is a life-threatening condition needing long poly-chemotherapy regimens. As no systematic reviews/meta-analysis is available to comprehensively evaluate the role of delamanid (DLM), we evaluated its effectiveness and safety.\ud \ud Methods\ud \ud We reviewed the relevant scientific literature published up to January 20, 2022. The pooled success treatment rate with 95% confidence intervals (CI) was assessed using a random-effect model. We assessed studies for quality and bias, and considered P0.05). The overall pooled treatment success rate in DLM and bedaquiline-containing regimens was 75.2% (95% CI 68.1-81.1) with no evidence of publication bias (Begg's test; P >0.05). In experimental studies the pooled treatment success rate of DLM-containing regimens was 72.5 (95% CI 44.2-89.8, P 0.05).\ud \ud Conclusions\ud \ud In MDR-TB patients receiving DLM, culture conversion and treatment success rates were high despite extensive resistance with limited adverse events.

Hepatocellular injury has been reported commonly in adults on rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) treatment. However, there are limited data in children.Two pharmacokinetic studies of children (0-17 years) routinely treated for RR/MDR-TB were conducted in Cape Town, South Africa between October 2011 and February 2020. Hepatocellular injury adverse events (AEs; defined as elevated alanine aminotransferase [ALT]) were documented serially. Data were analyzed to determine the incidence, etiology, risk factors, management and outcome of ALT elevation.A total of 217 children, median age 3.6 years (interquartile range, 1.7-7.1 years) at enrollment were included. The median follow-up time was 14.0 months (interquartile range, 9.8-17.2 months). Fifty-five (25.3%) patients developed an ALT AE. Of these, 43 of 55 (78%) patients had 54 ALT AEs attributed to their RR/MDR-TB treatment. The incidence rate of ALT AEs related to RR-TB treatment was 22.4 per 100 person-years. Positive HIV status and having an elevated ALT at enrollment were associated with time to ALT AE attributed to RR/MDR-TB treatment, with P values 0.0427 and P0.0001, respectively. Hepatitis A IgM was positive in 11 of 14 (78.6%) severe (grade ≥3) cases of ALT AEs. In 8 of 14 (57%) severe ALT AEs, hepatotoxic drugs were stopped or temporarily interrupted. None had a fatal or unresolved outcome.Hepatocellular injury in children on RR/MDR-TB treatment is common, although usually mild; having elevated ALT early in treatment and HIV-positive status are possible risk factors. Hepatitis A was a common etiology of severe ALT AE in children treated for RR/MDR-TB.

Background Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. Methods In this observational cohort study, children aged 6–17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described. Results Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5–16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia’s formula (QT) prolongation. Conclusions The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

Introduction The chest radiograph (CR) remains a key tool in the diagnosis of pediatric tuberculosis (TB). In children with presumptive intrathoracic TB, we aimed to identify CR features that had high specificity for, and were strongly associated with, bacteriologically confirmed TB. Methods We analyzed CR data from children with presumptive intrathoracic TB prospectively enrolled in a cohort study in a high-TB burden setting and who were classified using standard clinical case definitions as “confirmed,” “unconfirmed,” or “unlikely” TB. We report the CR features and inter-reader agreement between expert readers who interpreted the CRs. We calculated the sensitivity and specificity of the CR features with at least moderate inter-reader agreement and analyzed the relationship between these CR features and the classification of TB in a multivariable regression model. Results Of features with at least moderate inter-reader agreement, enlargement of perihilar and/or paratracheal lymph nodes, bronchial deviation/compression, cavities, expansile pneumonia, and pleural effusion had a specificity of > 90% for confirmed TB, compared with unlikely TB. Enlargement of perihilar (adjusted odds ratio [aOR]: 6.6; 95% confidence interval [CI], 3.80–11.72) and/or paratracheal lymph nodes (aOR: 5.14; 95% CI, 2.25–12.58), bronchial deviation/compression (aOR: 6.22; 95% CI, 2.70–15.69), pleural effusion (aOR: 2.27; 95% CI, 1.04–4.78), and cavities (aOR: 7.45; 95% CI, 3.38–17.45) were associated with confirmed TB in the multivariate regression model, whereas alveolar opacification (aOR: 1.16; 95% CI, .76–1.77) and expansile pneumonia (aOR: 4.16; 95% CI, .93–22.34) were not. Conclusions In children investigated for intrathoracic TB enlargement of perihilar or paratracheal lymph nodes, bronchial compression/deviation, pleural effusion, or cavities on CR strongly support the diagnosis.

Background Moxifloxacin is a recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics and QT interval prolongation and evaluate optimal dosing in children with RR-TB. Methods Pharmacokinetic data were pooled from 2 observational studies in South African children with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing. Results Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8–15] years); 16 (19%) were aged Conclusions Moxifloxacin doses above 10–15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when coadministered with other QT-prolonging agents.

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.

Delamanid has been demonstrated to be safe and effective for treatment of adult multidrug-resistant tuberculosis (MDR-TB) and has been approved by the European Commission for treatment of pediatric MDR-TB patients at least 10 kg in weight, making the drug no longer limited to adults. A 10-day phase I age deescalation study was conducted, followed by a 6-month phase II extension study, to assess the pharmacokinetics, safety, tolerability, and preliminary efficacy of delamanid when combined with optimized background regimen (OBR) in children (birth to 17 years) with MDR-TB. Delamanid administered at 100 mg twice-daily (BID), 50 mg BID, and 25 mg BID resulted in exposures in 12- to 17- ( n = 7), 6- to 11- ( n = 6), and 3- to 5-year-olds ( n = 12), respectively, comparable with those in adults at the approved adult dosage (100 mg BID).

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.

The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitation requires frequent update of existing guidelines. This review is aimed at providing clinicians and public health staff with an updated and easy-to-consult document arising from consensus of Global Tuberculosis Network (GTN) experts. The core published documents and guidelines have been reviewed including the recently published MDR-TB WHO rapid advice and ATS/CDC/ERS/IDSA guidelines. After a rapid review of epidemiology and risk factors, the clinical priorities on MDR-TB diagnosis (including whole genome sequencing and drug-susceptibility testing interpretations) and treatment (treatment design and management, TB in children) are discussed. Furthermore, the review comprehensively describes the latest information on contact tracing and LTBI management in MDR-TB contacts, while providing guidance on post-treatment functional evaluation and rehabilitation of TB sequelae, infection control and other public health priorities.

The diagnosis of abdominal tuberculosis (TB) is challenging, and the prevalence of abdominal TB in children is likely underestimated. It may present with nonspecific abdominal symptoms and signs, but children who present with pulmonary TB may have additional abdominal subclinical involvement. Diagnosis is specifically challenging because none of the available diagnostic tools provide adequate sensitivity and specificity. In this review, we summarize the best available evidence on abdominal TB in children, covering the epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment. We propose a diagnostic approach that could be followed for symptomatic children. We believe that a combination of investigations could be useful to both aid diagnosis and define the extent of the disease, and we propose that abdominal ultrasound should be used more frequently in children with possible TB and any abdominal symptoms. This neglected disease has received little attention to date, and further research is warranted.

There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.WHO Global TB Programme.For the French translation of the abstract see Supplementary Materials section.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB. Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided. Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

Children had better treatment outcomes and lower mortality rates than adults., Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (

Background Currently recommended treatment for multidrug-resistant (MDR) tuberculosis (TB) includes 4-8 months of an injectable medication, which is poorly tolerated. We evaluated the impact of coadministering lidocaine on pain and pharmacokinetics of intramuscular injections of amikacin in children with MDR-TB. Methods Children 8-18 years of age, receiving amikacin for MDR-TB treatment in Cape Town, South Africa, were eligible for this randomized crossover trial. Participants received a 15 mg/kg dose of intramuscular amikacin with and without additional lidocaine (0.2-0.4 mg/kg) on different days and were randomized to the order of the treatments (the sequence). Participants and staff completing evaluations were blinded to sequence. Samples were drawn predose, and at 1, 2, 4, 6 and 8 hours postdose for measurement of plasma amikacin concentrations. Pain was assessed by participants using the Wong Baker FACES pain scale (0-5) predose, immediately after the injection and then at 30 and 60 minutes. Pharmacokinetic measures were calculated using noncompartmental analysis. Results Twelve children were included, median age 11.5 years (interquartile range [IQR], 9.9-13.4 years). Participant-reported pain scores immediately after the amikacin injection were lower when lidocaine was coadministered: 1.0 (IQR, 0.5-2.0) with lidocaine versus 2.5 (1.0-4.0) without lidocaine (P = 0.004). The median area under the concentration time curve0-8 and median maximum plasma concentration of amikacin were 109.0 μg × h/mL (IQR, 84.7-121.3) and 36.7 μg/mL (IQR, 34.1-40.5) with lidocaine compared with 103.3 μg × h/mL (IQR, 81.7-135.0; P = 0.814) and 34.1 μg/mL (IQR, 35.6-46.4; P = 0.638) without lidocaine, respectively. Conclusions The coadministration of lidocaine resulted in reduced pain immediately after the injection and did not alter amikacin area under the concentration time curve or maximum plasma concentration.

BackgroundRifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children.ObjectivesTo characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB.Patients and methodsThe Opti-Rif trial enrolled dosing cohorts of 20 children aged 0–12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1–14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration–time curve from 0 to 24 h (AUC0–24) among adults receiving a 35 mg/kg dose].ResultsSixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4–11.7). Evaluated doses were ∼35 mg/kg (days 1–14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1–14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65–70 mg/kg rifampicin dose was needed in children to reach the target exposure.ConclusionsHigh rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.

We report a retrospective study on outcome of 14 newborn infants who received 62.5 times the recommended dose of Bacille Calmette-Guerin for immunization. All infants then received high-dose isoniazid and rifampicin (20 mg/kg/d each) as preventive therapy for 6 months. All had mild local adverse reactions, a third resolving within 16 weeks and all by 6 months.

Children affected by rifampicin-resistant tuberculosis (RR-TB; TB resistant to at least rifampicin) are a neglected group. Each year an estimated 25,000–30,000 children develop RR-TB disease globally. Improving case detection and treatment initiation is a priority since RR-TB disease is underdiagnosed and undertreated. Untreated paediatric TB has particularly high morbidity and mortality. However, children receiving TB treatment, including for RR-TB, respond well. RR-TB treatment remains a challenge for children, their caregivers and TB programmes, requiring treatment regimens of up to 18 months in duration, often associated with severe and long-term adverse effects. Shorter, safer, effective child-friendly regimens for RR-TB are needed. Preventing progression to disease following Mycobacterium tuberculosis infection is another key component of TB control. The last few years have seen exciting advances. In this article, we highlight key elements of paediatric RR-TB case detection and recent updates, ongoing challenges and forthcoming advances in the treatment of RR-TB disease and infection in children and adolescents. The global TB community must continue to advocate for more and faster research in children on novel and repurposed TB drugs and regimens and increase investments in scaling-up effective approaches, to ensure an equitable response that prioritises the needs of this vulnerable population.

Background Few studies have evaluated tuberculosis control in children and adolescents. We used routine tuberculosis surveillance data to quantify age- and human immunodeficiency virus (HIV)-stratified trends over time and investigate the relationship between tuberculosis, HIV, age, and sex. Methods All children and adolescents (0–19 years) routinely treated for drug-susceptible tuberculosis in South Africa and recorded in a de-duplicated national electronic tuberculosis treatment register (2004–2016) were included. Age- and HIV-stratified tuberculosis case notification rates (CNRs) were calculated in four age bands: 0–4, 5–9, 10–14, and 15–19 years. The association between HIV infection, age, and sex in children and adolescents with tuberculosis was evaluated using multivariable logistic regression. Results Of 719 400 children and adolescents included, 339 112 (47%) were 0–4 year olds. The overall tuberculosis CNR for 0–19 year olds declined by 54% between 2009 and 2016 (incidence rate ratio [IRR] = 0.46; 95% confidence interval [CI], .45–.47). Trends varied by age and HIV, with the smallest reductions (2013–2016) in HIV-positive 0–4 year olds (IRR = 0.90; 95% CI, .85–.95) and both HIV-positive (IRR = .84; 95% CI, .80–.88) and HIV-negative (IRR = 0.89; 95% CI, .86–.92) 15–19 year olds. Compared with 0- to 4-year-old males, odds of HIV coinfection among 15–19 year olds were nearly twice as high in females (adjusted odds ratio [aOR] = 2.49; 95% CI, 2.38–2.60) than in males (aOR = 1.35; 95% CI, 1.29–1.42). Conclusions South Africa’s national response to the HIV epidemic has made a substantial contribution to the observed declining trends in tuberculosis CNRs in children and adolescents. The slow decline of tuberculosis CNRs in adolescents and young HIV-positive children is concerning. Understanding how tuberculosis affects children and adolescents beyond conventional age bands and by sex can inform targeted tuberculosis control strategies.

Background Peripheral lymphadenopathy occurs often in children; fine needle aspiration biopsy (FNAB) is a commonly performed diagnostic procedure. We describe FNAB use and outcome for peripheral lymphadenopathy in children in a routine clinical setting. Methods A retrospective study done at Tygerberg Hospital, Cape Town of children ( Results Of the 173 children, the median age was 37 (interquartile range 13–75) months; 20 (11.5%) were HIV positive. Most FNABs were done in the neck (131; 76%) and axillary areas (34; 20%). FNAB provided a result in 165 (95%) cases; in 8 (5%) children FNAB was insufficient for diagnosis. Mycobacterial aetiology was diagnosed in 84 (49%); 49 (58%) were culture-confirmed (37 Mycobacterium tuberculosis, 10 Mycobacterium bovis BCG, 1 both and 1 non-tuberculous mycobacterium). Reactive lymphadenopathy was diagnosed in 56 (32%), neoplastic disease in 6 (3.5%) and other pathology in 19 (11%) cases. Additional special investigations changed FNAB diagnosis or led to an additional diagnosis in 8 (5%) children. Overall, 70/84 (83%) with mycobacterial aetiology and all neoplastic disease cases received the correct treatment. Follow-up appointments were arranged in 144 (83%) patients. Conclusions In a high tuberculosis burden area, a single FNAB provided a diagnosis in most cases in a routine referral setting; FNAB remains a safe and useful investigation. Follow-up of children to initiate appropriate treatment could improve. LAY SUMMARY Large swollen lymph nodes, especially in the neck, are a common finding in children. Fine needle aspiration biopsy (FNAB) is a commonly used diagnostic procedure and we looked at how well this procedure works in everyday hospital practice. We identified all children 80% of the mycobacterial pathology cases were correctly managed; the latter could definitely improve.

We determined mycobacterial drug resistance and HIV prevalence among children with bacteriologically confirmed tuberculosis (TB) from March 2013 to February 2017. Results were compared with 5 previous 2-year surveillance studies (2003-2013).Prospective surveillance of all bacteriologically confirmed TB in children (0-13 years) completed at Tygerberg Hospital, Cape Town, South Africa. Drug susceptibility testing was done by GenoType MTBDRplus for isoniazid and rifampicin; ofloxacin and amikacin drug susceptibility testing was completed if rifampicin resistance was detected. Xpert MTB/RIF was routinely introduced during this period.Six hundred sixty-two children, median age 34 months (interquartile range 14-79) had bacteriologically confirmed TB; 587 (88.7%) were culture-confirmed and 75 (11.3%) confirmed by Xpert MTB/RIF only. Of culture-confirmed cases, 509 (86.7%) were pan-susceptible, 47 (8.0%) were multidrug-resistant, 13 (2.2%) were RIF-resistant/INH-susceptible and 18 (3.1%) were INH-resistant/RIF-susceptible. Of Xpert-positive cases, 3/75 (4%), 68/75 (92%) and 4/75 (5%) were RIF-resistant, RIF-susceptible and RIF-indeterminate, respectively. Of 573 (97.6%) children tested, 74 (12.9%) were HIV positive. Compared with previous surveillance periods, RIF mono-resistance increased from 0% to 2.2% (trend test: χ = 7.050, P = 0.0079). HIV prevalence decreased from 29% to 10.6% (trend test: χ = 27.975, P0.0001). Of multidrug-resistant cases, 15/47 (32%) were ofloxacin resistant.The increase in RIF-resistant/INH-susceptible cases and ofloxacin resistance among multidrug-resistant TB cases in children, indicative of recent transmission, is concerning. The prevalence of multidrug-resistant TB remains high in children.

BACKGROUND Abdominal tuberculosis (TB) in children is poorly described and often poses a diagnostic challenge. We evaluated abdominal involvement in children presenting with bacteriologically confirmed TB. METHODS We undertook a retrospective study at Tygerberg Hospital, Cape Town, from January 1, 2014, through December 31, 2018, of all children (

Ethionamide has proven efficacy against both drug-susceptible and some drug-resistant strains of Mycobacterium tuberculosis. Limited information on its pharmacokinetics in children is available, and current doses are extrapolated from weight-based adult doses. Pediatric doses based on more robust evidence are expected to improve antituberculosis treatment, especially in small children. In this analysis, ethionamide concentrations in children from 2 observational clinical studies conducted in Cape Town, South Africa, were pooled. All children received ethionamide once daily at a weight-based dose of approximately 20 mg/kg of body weight (range, 10.4 to 25.3 mg/kg) in combination with other first- or second-line antituberculosis medications and with antiretroviral therapy in cases of HIV coinfection. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. The MDR-PK1 study contributed data for 110 children on treatment for multidrug-resistant tuberculosis, while the DATiC study contributed data for 9 children treated for drug-susceptible tuberculosis. The median age of the children in the studies combined was 2.6 years (range, 0.23 to 15 years), and the median weight was 12.5 kg (range, 2.5 to 66 kg). A one-compartment, transit absorption model with first-order elimination best described ethionamide pharmacokinetics in children. Allometric scaling of clearance (typical value, 8.88 liters/h), the volume of distribution (typical value, 21.4 liters), and maturation of clearance and absorption improved the model fit. HIV coinfection decreased the ethionamide bioavailability by 22%, rifampin coadministration increased clearance by 16%, and ethionamide administration by use of a nasogastric tube increased the rate, but the not extent, of absorption. The developed model was used to predict pediatric doses achieving the same drug exposure achieved in 50- to 70-kg adults receiving 750-mg once-daily dosing. Based on model predictions, we recommend a weight-banded pediatric dosing scheme using scored 125-mg tablets.

Safety concerns persist for long-term pediatric fluoroquinolone use. Seventy children (median age, 2.1 years) treated with levofloxacin 10–20 mg/kg once daily for multidrug-resistant tuberculosis (median observation time, 11.8 months) had few musculoskeletal events, no levofloxacin-attributed serious adverse events, and no Fridericia-corrected QT interval >450 ms. Long-term levofloxacin was safe and well tolerated.

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.

Three-hundred four young children with suspected pulmonary tuberculosis had a gastric aspirate, induced sputum and nasopharyngeal aspirate collected on each of 2 consecutive weekdays. Specimens collected on the second day were pooled in the laboratory for each child individually. The diagnostic yield by Xpert and culture from pooled specimens was not significantly different to a single gastric aspirate.

Background Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Methods and findings Children routinely treated for MDR-TB in 2 observational studies (2011–2015, 2016–2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data. Conclusions Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated., Using data from two cohorts, Anthony Garcia-Prats and colleagues model the appropriate dosing necessary to achieve target concentrations for linezolid to treat children with multidrug-resistant tuberculosis., Author summary Why was this study done? Linezolid is an antibiotic that has recently been repurposed for the treatment of multidrug-resistant tuberculosis (MDR-TB). Based on emerging data from clinical trials, it is now recommended for inclusion as a priority in treatment regimens for adults and children. There is a lack of evidence-based dosing guidelines for linezolid in children for MDR-TB. Linezolid has frequent adverse effects that are associated with higher doses and longer durations of treatment, but this has not been well described in children treated for MDR-TB. What did the researchers do and find? We assessed linezolid pharmacokinetics (concentrations) and safety among children routinely treated for MDR-TB from 2 observational studies. We modelled this pharmacokinetic data and simulated the doses in children that would be needed to achieve current targets. Doses supported by our data for some weight bands were lower than currently in use, which may reduce the risk of adverse effects. Linezolid-related adverse effects were frequent—with low haemoglobin being the most common—and occasionally severe (grade 3 or 4). What do these findings mean? Revised linezolid doses supported by this study now provide an evidence base for international dosing recommendations. All linezolid-treated children with MDR-TB should have careful safety monitoring to include at least regular haemoglobin monitoring. Larger studies, evaluating the revised dosing, are needed to better characterise linezolid safety and to assess the risk of more rare linezolid-related events, especially given the small number of children in this study.

This study characterized the pharmacokinetics of novel 100-mg levofloxacin dispersible tablets in 24 children aged

Background Little is known about the course and management of perinatal tuberculosis (TB). We describe the presentation, medical and surgical management of culture-confirmed TB in infants younger than 3 months of age. Methods We conducted a retrospective study including all infants younger than 3 months of age with culture-confirmed TB admitted to Tygerberg Hospital, Cape Town, South Africa, from March 2003 to June 2015. Results During the study period, 106 of 2017 (5%) children younger than 13 years of age with culture-confirmed TB were infants younger than 3 months of age. The median age on admission was 67 days (interquartile range, 40-79). Intrathoracic TB was present in 101 (95%) infants; of these, 34 (32%) had extrathoracic TB. Two (2%) infants had extrathoracic TB only, while 3 (3%) infants were asymptomatic and diagnosed as having TB infection only. Forty (38%) infants were HIV-exposed, and 14 (13%) were HIV-infected. The mother was identified as the source case in 53 (50%) infants. Mycobacterium tuberculosis was cultured in a median of 2 (interquartile range, 1-7) specimens per infant; 9 (9%) had drug-resistant TB. Bronchoscopy was done in 37 (35%) infants, and 27 (26%) underwent intrathoracic lymph node decompression. Twelve (11%) infants died during admission, 81(76%) were clinically stable on transfer or discharge from hospital, and outcome was not documented in 13 (12%) infants. Conclusions TB in young infants often presents with severe intrathoracic disease, including airway compression. Bronchoscopy may aid confirmation of the diagnosis and management; decompression of intrathoracic lymph nodes was common. Mortality in this age group remains high.

Levofloxacin is used for the treatment and prevention of multidrug-resistant tuberculosis in children, but current adult formulations are poorly palatable. A questionnaire administered to caregivers of 27 children taking a novel 100 mg dispersible taste-masked levofloxacin tablet found the new formulation to be more palatable (69%) and easier to prepare (81%) than the adult formulation. This formulation may assist children to better adhere to anti-tuberculous therapy.

Background An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. Methods and findings To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged, In a systematic review and meta-analysis conducted to inform World Health Organization guidelines, Elizabeth Harausz and colleagues investigate different treatment regimens and outcomes for children with multidrug-resistant tuberculosis., Author summary Why was this study done? Treatment for multidrug-resistant tuberculosis (MDR TB) affects 32,000 children per year, requires longer treatment with much more toxic medications than drug-susceptible tuberculosis. Unfortunately, little is know about the optimal treatment for children with MDR TB. This study reviewed treatment and outcome data from children around the world in order to better understand the management of MDR-TB in children. This study also sought to understand the risk factors for poor treatment outcomes in children with MDR-TB. This study informed the World Health Organization guidelines on treatment of MDR-TB in children. What did the researchers do and find? We performed a systematic review and individual patient data meta-analysis on clinical characteristics and treatment outcomes on 975 children from across 18 countries. Children were analyzed in two separate groups, those with bacteriologically confirmed MDR-TB and those who were clinically diagnosed with MDR-TB. We found that, in general, children do well when treated with the second-line MDR-TB medications (78% overall had successful treatment outcomes), despite the fact that there was a high burden of severe disease. Malnutrition and not being treated for HIV (if the child was HIV-positive) during TB treatment significantly increased the risk of poor outcomes. Second-line injectable agents and high-dose isoniazid were associated with treatment success. However, a high proportion of children with non-severe disease who received no second-line injectable agents still did well; therefore, children with non-severe disease may be able to be spared from these toxic medications. What do these findings mean? Consideration should be given to using high-dose isoniazid in treatment regimens, and if children have non-severe disease, the possibility of excluding second-line injectable agents from the treatment regimen should be considered. HIV treatment should be started as soon as is possible, and malnutrition should be aggressively treated.

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.

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.

The relative fitness of organisms causing drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) is unclear. We compared the risk of TB infection and TB disease in young child household contacts of adults with confirmed DS-TB and MDR-TB.In this cross-sectional analysis we included data from two community-based contact cohort investigation studies conducted in parallel in Cape Town, South Africa. Children5 years of age with household exposure to an infectious TB case were included between August 2008 to June 2011. Children completed investigation for TB infection (tuberculin skin test) and TB disease (symptom evaluation, chest radiograph, bacteriology) in both studies using standard approaches. The impact of MDR-TB exposure on each covariate of TB infection and TB disease was assessed using univariable and multivariable logistic regression.Of 538 children included, 312 had DS-TB and 226 had MDR-TB exposure. 107 children with DS-TB exposure had TB infection (34.3%) vs. 101 (44.7%) of children with MDR-TB exposure (adjusted Odds Ratio [aOR]: 2.05; 95% confidence interval [CI]: 1.34-3.12). A total of 15 (6.6%) MDR-TB vs. 27 (8.7%) DS-TB child contacts had TB disease at enrolment (aOR: 0.43; 95% CI: 0.19-0.97).Our results suggest a higher risk of TB infection in child contacts with household MDR-TB vs. DS-TB exposure, but a lower risk of TB disease. Although potentially affected by residual confounding or selection bias, our results are consistent with the hypothesis of impaired virulence in MDR-TB strains in this setting.

Background The relative fitness of organisms causing drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) is unclear. We compared the risk of TB infection and TB disease in young child household contacts of adults with confirmed DS-TB and MDR-TB. Methods In this cross-sectional analysis we included data from two community-based contact cohort investigation studies conducted in parallel in Cape Town, South Africa. Children

Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

Current data on tuberculous pericardial effusion in children are limited. In this study, the cases of 30 children with tuberculous pericardial effusion were reviewed retrospectively. The prevalence of human immunodeficiency virus and of culture-confirmed tuberculosis was high. Chest radiography provided lower diagnostic sensitivity than sonography but detected all large and complicated effusions. Outcomes were generally good, and residual complications were mainly due to comorbidity.

Purpose of review Childhood multidrug-resistant (MDR) tuberculosis is an emerging disease with increasing numbers being recognized. This review presents recent developments in childhood MDR tuberculosis. Recent findings New molecular-based diagnostic tests, although not optimal, have reduced the difficulty in confirming the diagnosis of MDR tuberculosis in children. However, the importance of making a diagnosis of probable MDR tuberculosis has been reaffirmed by contact tracing studies showing 80-90% of child contacts of MDR tuberculosis cases who develop disease have MDR tuberculosis themselves. Prevention of MDR tuberculosis in child contacts with appropriate preventive treatment regimens is supported by new observational data and deserves further study. When diagnosed and treated appropriately, outcomes for MDR tuberculosis and even extensively drug-resistant tuberculosis in children are good, despite limited pharmacokinetic data on second-line drugs. Novel anti-tuberculosis drugs and regimens are becoming available and should be studied in children for dose-finding and safety. Recording and reporting of MDR tuberculosis in children are frequently poor, leading to inaccurate estimates of disease burden and suboptimal resource planning. Summary Rapid diagnosis and appropriate treatment results in good outcomes in the majority of children with MDR tuberculosis. Additional research on optimal diagnosis, prevention and treatment of MDR tuberculosis in children remains a high priority.

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.

The aminoglycosides and polypeptides are vital drugs for the management of multidrug-resistant (MDR) tuberculosis (TB). Both classes of drug cause hearing loss. We aimed to determine the extent of hearing loss in children treated for MDR-TB.In this retrospective study, children (15 years) admitted to Brooklyn Chest Hospital, Cape Town, South Africa, from January 2009 until December 2010, were included if treated for MDR-TB with injectable drugs. Hearing was assessed and classified using audiometry and otoacoustic emissions.Ninety-four children were included (median age: 43 months). Of 93 tested, 28 (30%) were HIV-infected. Twenty-three (24%) children had hearing loss. Culture-confirmed, as opposed to presumed, diagnosis of TB was a risk factor for hearing loss (OR: 4.12; 95% CI: 1.13-15.0; p = 0.02). Seven of 11 (64%) children classified as having hearing loss using audiometry had progression of hearing loss after finishing the injectable drug.Hearing loss is common in children treated for MDR-TB. Alternative drugs are required for the treatment of paediatric MDR-TB.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Fluoroquinolones are a key component of multidrug-resistant tuberculosis treatment. We describe the first reported case of probable levofloxacin-associated intracranial hypertension in a 6-year-old girl with pulmonary multidrug-resistant tuberculosis. The case highlights the potential risk of secondary intracranial hypertension in multidrug-resistant tuberculosis patients who require prolonged fluoroquinolone therapy and the need for ophthalmologic screening in children with suggestive signs and symptoms.

Summary Children exposed to multidrug-resistant (MDR) Mycobacterium tuberculosis are at risk of developing MDR tuberculosis. Where treatment is available, it is lengthy, expensive, and associated with poor adherence and notable morbidity and mortality. Preventive treatment effectively lowers the risk of disease progression for contacts of individuals with drug-susceptible tuberculosis, but this strategy is poorly studied for contacts of people with MDR tuberculosis. In this Review we discuss the management of child contacts of source cases with MDR tuberculosis. We pay particular attention to assessment, existing international guidelines, possible preventive treatments, rationales for different management strategies, and the interaction with and implications of HIV infection.

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.

Drug-resistant Mycobacterium tuberculosis (TB) infection represents a serious and growing problem. For patients infected or suspected of being infected with multidrug or extensively drug-resistant TB, several medications have to be given simultaneously for prolonged periods. Here, we review the literature on treatment and monitoring of adverse effects of pediatric drug-resistant TB therapy in a high resource, low TB burden setting.

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.

Although awareness is growing, childhood tuberculosis (TB) remains a neglected disease in many resource-limited settings. In part this reflects operational difficulties, lack of visibility in official reports, as well as perceptions that children tend to develop mild disease, contribute little to disease transmission, and do not affect epidemic control. At an international level there is greater appreciation that children contribute significantly to the global TB disease burden and suffer severe TB-related morbidity and mortality, particularly in TB-endemic areas, where the disease often remains undiagnosed. However, this is not always the case at the national or local level and there remains an urgent need for feasible and implementable policies to guide clinical practice. Pediatric TB can be regarded as an emerging epidemic in areas where the adult epidemic remains out of control and Mycobacterium tuberculosis transmission is ongoing. This article reviews important concepts, challenges, and management principles related to childhood TB; it also summarizes the main priorities for future research.

Objectives: Bacille Calmette-Guerin (BCG), a live attenuated Mycobacterium bovis vaccine, poses a risk to human immunodeficiency virus (HIV)-infected children; this risk has not been well quantified. We estimate the risk of disseminated BCG disease in HIV-infected children in a setting highly endemic for tuberculosis and HIV. Design and methods: We conducted a prospective hospital-based surveillance study in the Western Cape Province, South Africa. Clinical and laboratory-confirmed cases of disseminated BCG disease in children

Drug-resistant tuberculosis is a threat to tuberculosis control programs and community health. This growing problem mirrors the increasing incidence of tuberculosis in general. Public health problems include the absence of early diagnosis and effective treatment. The real need is to identify tuberculosis patients far earlier, particularly those with drug-resistant strains, and to begin appropriate therapy, which is of the shortest possible duration with minimal risk of acquiring further drug resistance or permitting further transmission. This article will address the epidemic of drug resistance and discuss some of the inherent difficulties in the treatment of drug-resistant tuberculosis. We highlight some of the controversies and new findings in this area, as well as future perspectives requiring more active interventions, in addition to new technology and developments.