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Drug-resistant (DR) strains of Mycobacterium tuberculosis ( M . tb ) are increasingly recognised as a threat to global tuberculosis (TB) control efforts. Identifying people with DR-TB exposure/ infection and providing TB preventive therapy (TPT) is a public health priority. TB guidelines advise the evaluation of household contacts of newly diagnosed TB cases, with the provision of TPT to vulnerable populations, including young children (<5 years). Many children become infected with TB through exposure in their household. Levofloxacin is under evaluation as TPT in children exposed to M . tb strains with resistance to rifampicin and isoniazid (multidrug-resistant TB; MDR-TB). Prior to opening a phase 3 prevention trial in children <5 years exposed to MDR-TB, the pharmacokinetics and safety of a novel formulation of levofloxacin given daily was evaluated as part of a lead-in study. We conducted an exploratory qualitative study of 10 caregivers’ experiences of administering this formulation. We explored how the acceptability of levofloxacin as TPT is shaped by the broader impacts of MDR-TB on the overall psychological, social, and financial wellbeing of caregivers, many of whom also had experienced MDR-TB. Caregivers reported that the novel levofloxacin formulation was acceptable. However, caregivers described significant psychosocial challenges in the process of incorporating TPT administration to their children into their daily lives, including financial instability, withdrawal of social support and stigma. When caregivers themselves were sick, these challenges became even more acute. Although new child-friendly formulations can ameliorate some of the pragmatic challenges related to TPT preparation and administration, the overall psychosocial burden on caregivers responsible for administering TPT remains a major determinant of effective MDR-TB prevention in children.

In this randomized, controlled trial involving children with household exposure to multidrug-resistant tuberculosis, levofloxacin led to a lower incidence of tuberculosis than placebo, but the difference was not significant.

Local Community Advisory Boards (CABs), local healthcare services, and the South African National TB Programme (NTP) were consulted during trial planning. Key audiences, including trial teams, policy partners, global clinical and scientific audiences, healthcare providers, industry, local TB control programmes, affected communities, lay audiences, and trial participants and families, were identified early, and specific strategies targeting each group were outlined in a Research Impact Strategy document. Tokens of appreciation—mugs branded with relevant logos and a QR code link to trial results and updated South African and WHO TB prevention guidelines—were distributed at all facilities. In Johannesburg, the trial team presented the results to the Johannesburg Primary Health Care Management committee, which oversees facilities where recruitment took place.

Background Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment. Methods The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15–20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18–24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial. Discussion If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy. Trial registration ISRCTN Registry, ISRCTN92634082 . Registered on 31 March 2016.

Background Tuberculosis (TB)-associated mortality in South Africa remains high. This review aimed to systematically assess risk factors associated with death during TB treatment in South African patients. Methods We conducted a systematic review of TB research articles published between 2010 and 2018. We searched BioMed Central (BMC), PubMed®, EBSCOhost, Cochrane, and SCOPUS for publications between January 2010 and December 2018. Searches were conducted between August 2019 and October 2019. We included randomised control trials (RCTs), case control, cross sectional, retrospective, and prospective cohort studies where TB mortality was a primary endpoint and effect measure estimates were provided for risk factors for TB mortality during TB treatment. Due to heterogeneity in effect measures and risk factors evaluated, a formal meta-analysis of risk factors for TB mortality was not appropriate. A random effects meta-analysis was used to estimate case fatality ratios (CFRs) for all studies and for specific subgroups so that these could be compared. Quality assessments were performed using the Newcastle-Ottawa scale or the Cochrane Risk of Bias Tool. Results We identified 1995 titles for screening, 24 publications met our inclusion criteria (one cross-sectional study, 2 RCTs, and 21 cohort studies). Twenty-two studies reported on adults ( n  = 12561) and two were restricted to children < 15 years of age ( n  = 696). The CFR estimated for all studies was 26.4% (CI 18.1–34.7, n  = 13257 ); 37.5% (CI 24.8-50.3, n  = 5149) for drug-resistant (DR) TB; 12.5% (CI 1.1–23.9, n  = 1935) for drug-susceptible (DS) TB; 15.6% (CI 8.1–23.2, n  = 6173) for studies in which drug susceptibility was mixed or not specified; 21.3% (CI 15.3-27.3, n  = 7375) for people living with HIV/AIDS (PLHIV); 19.2% (CI 7.7–30.7, n  = 1691) in HIV-negative TB patients; and 6.8% (CI 4.9–8.7, n  = 696) in paediatric studies. The main risk factors associated with TB mortality were HIV infection, prior TB treatment, DR-TB, and lower body weight at TB diagnosis. Conclusions In South Africa, overall mortality during TB treatment remains high, people with DR-TB have an elevated risk of mortality during TB treatment and interventions to mitigate high mortality are needed. In addition, better prospective data on TB mortality are needed, especially amongst vulnerable sub-populations including young children, adolescents, pregnant women, and people with co-morbidities other than HIV. Limitations included a lack of prospective studies and RCTs and a high degree of heterogeneity in risk factors and comparator variables. Systematic review registration The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018108622. This study was funded by the Bill and Melinda Gates Foundation (Investment ID OPP1173131) via the South African TB Think Tank.

To the Editor: The articles by Fox et al. 1 and Hesseling et al. 2 and the editorial by Dorman 3 (Dec. 19/26 issue) on the use of levofloxacin for tuberculosis prevention underscore the many difficulties that investigators face when approaching populations at risk. Despite the strengths of the trials, the pill-counting and questionnaire methods that were used to assess adherence are known to have numerous shortcomings. 4 Given the multiple difficulties in conducting these trials, was any effort made to measure blood drug levels in trial participants? Because differences in adherence, absorption, and metabolism may play an important role in trial outcomes, pharmacokinetic . . .

Avian nectarivores face the dilemma of having to conserve salts while consuming large volumes of a dilute, electrolyte-deficient diet. This study evaluates the responses to salt solutions and the regulation of salt intake in white-bellied sunbirds ( Cinnyris talatala ) and New Holland honeyeaters ( Phylidonyris novaehollandiae ). Birds were first offered a choice of four sucrose diets, containing no salt or 25, 50 or 75 mM NaCl. The experiment was repeated using five sucrose concentrations (0.075–0.63 M) as the base solution. Both species ingested similar amounts of all diets when fed the concentrated base solutions. However, when birds had to increase their intake to obtain enough energy on the dilute sucrose diets, there was a general avoidance of the higher salt concentrations. Through this diet switching, birds maintained constant intakes of both sucrose and sodium; the latter may contribute to absorption of their sugar diets. A second, no-choice experiment was designed to elucidate the renal concentrating abilities of these two nectarivores, by feeding them 0.63 M sucrose containing 5–200 mM NaCl over a 4-h trial. In both species, cloacal fluid osmolalities increased with diet NaCl concentration, but honeyeaters tended to retain ingested Na + , while sunbirds excreted it. Comparison of Na + and K + concentrations in ureteral urine and cloacal fluid showed that K + , but not Na + , was reabsorbed in the lower intestine of both species. The kidneys of sunbirds and honeyeaters, like those of hummingbirds, are well suited to diluting urine; however, they also appear to concentrate urine efficiently when necessary.

Nectar-feeding birds ingest excess water and risk loss of solutes when they excrete it. Previous work has shown that white-bellied sunbirds (Cinnyris talatala) are unable to maintain energy balance on extremely dilute sucrose diets without salts (e.g. <0.25 mol l⁻¹), and that they lose more electrolytes (i.e. Na⁺ and K⁺) via cloacal fluid on these diets than on more concentrated diets. Using white-bellied sunbirds and New Holland honeyeaters (Phylidonyris novaehollandiae) we tested the effect of adding electrolytes to a 0.1 mol l⁻¹ sucrose diet, by including equimolar NaCl and KCl at concentrations from 5 to 40 mmol l⁻¹ and the individual salts at 20 mmol l⁻¹. Addition of salts enabled both species to drink significantly more of the 0.1 mol l⁻¹ sucrose diet than in the absence of salts, and mass loss during the experiment was reduced when salt was included. The larger honeyeaters may be more susceptible to electrolyte depletion than the smaller sunbirds. On 20 mmol l⁻¹ combined salts, both sunbirds and honeyeaters consumed eight times their body mass in fluid daily. KCl alone had no effect. Birds are thus limited in their consumption of extremely dilute diets by increasing losses of Na⁺. This was confirmed by measuring plasma Na⁺ levels, which decreased in both species in the absence of dietary Na⁺. In addition, sucrose assimilation efficiencies were slightly, but significantly lower when sunbirds were fed salt-free diet, while glucose levels in ureteral urine remained extremely low. It is concluded that Na⁺ depletion on very dilute salt-free diets does not affect Na⁺-glucose transport activity in the kidney, but interferes with sugar digestion and/or assimilation in the intestine.