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- ItemAbacavir Exposure in Children Cotreated for Tuberculosis with Rifampin and Superboosted Lopinavir-Ritonavir(2020-05) Rabie, Helena; Tikiso, Tjokosela; Lee, JaniceABSTRACT In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopi-navir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interac-tions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing 15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of anti-tuberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treat-ment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treat-ment with rifampin and LPV/r-4:4 but remained within the median adult recom-mended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased dur-ing concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.)
- ItemAcquired neonatal bronchial stenosis after selective intubation : successful managed with balloon dilatation(Wiley Open Access, 2019) Goussard, Pierre; Morrison, Julie; Bekker, Adrie; Fourie, BarendENGLISH ABSTRACT: Premature babies are prone to airway‐related complications. Selective intubation for the management of pulmonary interstitial emphysema may cause acquired bronchial stenosis. Balloon dilatation under fluoroscopy is a safe minimal invasive and successful intervention for acquired bronchial stenosis. Follow‐up bronchoscopy is needed due to risk of restenosis.
- ItemAddressing critical knowledge gaps to improve and shorten multidrug-resistant tuberculosis treatment regimens in children(Stellenbosch : Stellenbosch University, 2018-12) Garcia-Prats, Anthony Joseph; Hesseling, Anneke Catharina; Schaaf, Hendrik Simon; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.ENGLISH ABSTRACT: Multidrug-resistant (MDR) tuberculosis (TB), defined as TB disease or infection caused by Mycobacterium tuberculosis with resistance to at least both isoniazid and rifampicin, threatens global TB control, with an estimated 490,000 incident cases of MDR-TB globally in 2016. The burden of paediatric MDR-TB has been poorly characterized to date. However, recent modeling studies estimate that there are approximately 26,000- 32,000 incident MDR-TB cases in children (< 15 years of age) worldwide each year. Traditionally, treatment regimens for adults and children were constructed using a minimum of four second-line antituberculosis drugs likely to be effective, including a second-line injectable medication, for up to 6 months, and a total duration of treatment of up to 18-24 months. In 2016, the World Health Organization (WHO) recommended a shortened (9-12 month) treatment regimen, which still includes an injectable drug for four months. In addition, the development and increasing use of the novel TB drugs bedaquiline and delamanid, are radically altering the MDR-TB treatment landscape, although children have lagged behind in accessing these important developments. Treatment outcomes for adults with MDR-TB have been persistently poor, with 54% successfully treated in 2014 both overall globally, and in South Africa. In contrast, treatment outcomes among children with MDR-TB are generally good, with 78-90% successfully treated under routine clinical conditions. However, current paediatric MDR-TB treatment regimens have important limitations. These current regimens remain long (9-18 months or more), which is costly and burdensome. There are also frequent adverse effects, including from the second-line injectable medications (amikacin, kanamycin, capreomycin) that cause permanent sensorineural hearing loss in up to 24% of children treated long-term. Additionally, the injectables are mainly given by painful daily intramuscular injections, resulting in trauma and distress for patients, their caregivers and healthcare providers. Therefore, it is an urgent priority to develop more optimal treatment regimens for children with MDR-TB that retain their efficacy but are shorter, more child-friendly, are better tolerated, safer and which do not require the use of an injectable medication. The purpose of this doctoral research was to address critical knowledge gaps in paediatric MDR-TB treatment, with the aim of informing more effective, safer, and more child-friendly MDR-TB treatment strategies in children. I identified critical knowledge gaps related to the pharmacokinetics, including the effects of formulation, optimal dosing, safety, and tolerability of key second-line and novel antituberculosis drugs in children, and completed complementary studies on ofloxacin, levofloxacin, linezolid, amikacin and bedaquiline designed to address these knowledge gaps. In an observational study of the pharmacokinetics and safety of ofloxacin in children routinely treated for MDR-TB disease or exposure, exposures after a daily 20mg/kg ofloxacin dose were well below target exposures from adults receiving the routine 800 mg dose. Ofloxacin was safe and well tolerated, with few musculoskeletal complaints or serious adverse events. This data adds to the evidence of the safety of fluoroquinolones in children even with long-term use, and identifies the need to revise ofloxacin paediatric doses. Subsequently, in this large observational study, the population pharmacokinetics of levofloxacin among children with MDR-TB disease or exposure was characterized using non-linear mixed effects modeling. One hundred and nine children treated with the routinely available adult 250 mg tablet formulation of levofloxacin at daily doses of 15 mg/kg or 20 mg/kg were included. Levofloxacin’s apparent oral clearance (CL/F) was higher than expected based on previously published data, possibly due to the formulation studied. Simulations using the final model targeting exposures in adults with TB receiving 750 mg of levofloxacin identified weight-banded doses that were much higher than previously in use (18 mg/kg to nearly 40 mg/kg daily). It was concluded that levofloxacin dosing in children should be reassessed, formulation effects explored further, and that safety should be carefully evaluated if higher levofloxacin doses are used. Building on this data, I completed an evaluation of the safety of long-term levofloxacin in children treated for MDR-TB. Among 70 children, median age 2.1 years, treated for a median of 11.6 months, levofloxacin was generally safe and was well tolerated. There were no Grade 4 or serious adverse events, and few musculoskeletal events. There was no QT-interval prolongation and no association of QT interval with levofloxacin concentration. This study supported the safety of long-term fluoroquinolone treatment in children, and provided novel data on the QT prolonging effect of levofloxacin, which is needed, as increasingly levofloxacin is being combined with other QT prolonging medications. The effects of drug formulation in pharmacokinetic studies are critically important. In a lead-in pharmacokinetics study to the TB-CHAMP trial (phase 3 cluster randomized trial comparing levofloxacin vs. placebo for prevention of TB in child contacts of MDR-TB cases), 24 children had pharmacokinetic sampling with a novel dispersible tablet formulation of levofloxacin. The levofloxacin exposures were much higher with this novel formulation compared to those seen in the previously reported study using the adult 250 mg levofloxacin tablet. Combining these two data sets using non-linear mixed effects modeling identified that reduced bioavailability of the adult 250 mg tablet formulation compared to the dispersible levofloxacin tablet was the explanation for the substantial differences in exposures. This study highlighted the importance of formulation considerations to paediatric pharmacokinetic studies and provided practical weight-banded dosing guidelines for use of this formulation now becoming available in the field. Linezolid is a key drug with an increasingly important role in the treatment of MDR-TB strains with additional resistance and in central nervous system TB disease. I performed a structured review of the literature on linezolid to inform its use in children for MDR-TB treatment and identify knowledge gaps for future research. Few children treated with linezolid for MDR-TB were described in the literature. As in adults, linezolid appeared to be effective but was associated with frequent adverse events. There was no data on linezolid pharmacokinetics in children with TB. Practical interim guidance was provided for linezolid use in children. Priority research needs identified included studying linezolid pharmacokinetics in children with TB, characterization of its safety with long-term use, and its optimal dose for TB in MDR-TB regimens going forward. Following on this review, an analysis of linezolid pharmacokinetics and safety from children with MDR-TB was performed with data from 48 children combined from two observational studies using non-linear mixed effects modeling. Seventeen children received long-term linezolid and were monitored longitudinally for safety; 31 children only contributed cross-sectional pharmacokinetic data after a single-dose of linezolid. After accounting for the effects of weight with allometric scaling, no other covariates significantly contributed to the model. Exposures were higher than expected, based on previously reported data. Ten of 17 participants had a linezolid related adverse event, including five Grade 3 or 4 events; anaemia was the most common event. This first data on linezolid pharmacokinetics in children demonstrated higher than expected exposures and frequent, serious linezolid-related adverse events, and will inform the use and future dosing recommendations of this increasingly important antituberculosis medication in children. While drug substitutions for injectable drugs are not yet available for many children, improving the tolerability of the continued use of second-line injectable medications is an important question to address in children. A randomized two-period crossover study was designed to characterize the effect of co-administration of lidocaine on the pain and pharmacokinetics of intramuscular amikacin. Children each received a dose of amikacin with and without additional lidocaine on separate days, and were randomized to the sequence of treatments; pain assessments and pharmacokinetic sampling were performed on each day. Twelve children were enrolled and completed the study. The addition of lidocaine reduced pain immediately after the injection, was safe, and did not affect the pharmacokinetics of amikacin in children, and should be considered as a routine policy in patients with MDR-TB receiving an injectable agent. The novel drug bedaquiline is increasingly used globally and in South Africa for adults with MDR-TB, and ongoing paediatric trials will characterize the pharmacokinetics, safety and optimal dose in children. The paediatric formulation, which is being evaluated in at least one of the ongoing paediatric trials, may not be available for routine care for some time. In order to inform the rational use of the adult bedaquiline formulation in young children, a randomized two-period crossover study in healthy adult volunteers was designed. Adult bedaquiline tablets administered suspended in water were bioequivalent to adult tablets swallowed whole. The suspended tablets were also found to be acceptable and palatable to the majority of participants, an important finding considering that crushing or suspending some tablets, such as the fluoroquinolones, reduces their palatability and acceptability substantially. This data will accelerate access to bedaquiline for young children in research and routine care. In conclusion, this doctoral research has addressed a number of important key knowledge gaps related to more optimal paediatric MDR-TB treatment. This research has raised a number of follow-up questions that have informed subsequent studies that will continue to advance the field towards a goal of effective, safe, shorter MDR-TB treatment for all children.
- ItemAdherence to isoniazid preventive chemotherapy: a prospective community based study(BMJ Publishing Group, 2006-09) Marais, B. J.; Van Zyl, S.; Schaaf, H. Simon; Van Aardt, M. C.; Gie, R. P.; Beyers, NuldaBackground: Current international guidelines recommend 6–9 months of isoniazid (INH) preventive chemotherapy to prevent the development of active tuberculosis in children exposed to a susceptible strain of M tuberculosis. However, this is dependent on good adherence and retrospective studies have indicated that adherence to unsupervised INH preventive chemotherapy is poor. Aim: To prospectively document adherence to six months of unsupervised INH monotherapy and outcome in children with household exposure to an adult pulmonary tuberculosis index case. Methods: From February 2003 to January 2005 in two suburbs of Cape Town, South Africa, all children <5 years old in household contact with an adult pulmonary tuberculosis index case were screened for tuberculosis and given unsupervised INH preventive chemotherapy once active tuberculosis was excluded. Adherence and outcome were monitored. Results: In total, 217 index cases from 185 households were identified; 274 children <5 years old experienced household exposure, of whom 229 (84%) were fully evaluated. Thirty eight children were treated for tuberculosis and 180 received preventive chemotherapy. Of the children who received preventive chemotherapy, 36/180 (20%) completed ⩾5 months of unsupervised INH monotherapy. During the subsequent surveillance period six children developed tuberculosis: two received no preventive chemotherapy, and four had very poor adherence. Conclusion: Adherence to six months of unsupervised INH preventive chemotherapy was poor. Strategies to improve adherence, such as using shorter duration multidrug regimens and/or supervision of preventive treatment require further evaluation, particularly in children who are at high risk to progress to disease following exposure.
- ItemAdolescent tuberculosis(Health & Medical Publishing Group, 1996-3) Donald, P. R.; Beyers, Nulda; Rook, G. A. W.INTRODUCTION: One of the most intriguing features of the epidemiology of tuberculosis is the well-known variation in the age incidence of disease and the variation in the nature of the disease with age. During infancy and early childhood, tuberculous disease is particularly liable to follow infection and high morbidity and mortality are experienced. Disseminated forms of disease, such as miliary tuberculosis and tuberculous meningitis, are particularly likely to develop.
- ItemAdrenal rest tumours in congenital adrenal hyperplasia(Journal of Endocrinology, Metabolism and Diabetes of South Africa (JEMDSA), 2008-07) Zollner, Ekkehard W.; Pitcher, RichardClassic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is rare, occurring approximately once in every 15 000 live births.1 At birth it is often suspected in girls because of ambiguous genitalia, whereas boys have normal genitalia. The salt-losing type of CAH presents with adrenal crisis a few weeks after birth, while the simple type manifests virilisation and rapid growth years later. The diagnosis is confirmed by an elevated plasma 17-hydroxyprogesterone (17- OHP) level. Additional features in the salt-losing variety are hyponatraemia, hyperkalaemia, metabolic acidosis and an elevated plasma renin level. The gluco- and mineralocorticoid insufficiency is corrected by providing hydrocortisone and fludrocortisone, respectively. It may be necessary to add sodium chloride to infant feeds. Treatment is lifelong. If compliance is poor, excess androgen production, accelerated growth, secondary central precocious puberty and, in boys, adrenal rest tumours can occur, as in the following case.
- ItemThe aetiology of hypophosphatemia in children recovering from Kwashiorkor(Stellenbosch : Stellenbosch University, 2015-12) Nicol, Simone; Nel, Etienne De la Rey; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child HealthENGLISH ABSTRACT : Abstract Background The aetiology of hypophosphatemia in children recovering from kwashiorkor is poorly understood. Current theory of the pathophysiology of hypophosphatemia due to refeeding syndrome in adults describes intracellular phosphate trapping, mediated by a metabolic shift from lipid-based catabolism to carbohydrate metabolism. Treatment of hypophosphatemia associated with severe acute malnutrition (SAM) presents a challenge to the control of serum phosphate levels. Hypothesis This study explores the hypothesis that hypophosphatemia is caused by impaired renal tubular phosphate reabsorption in children recovering from oedematous malnutrition. Study Design A prospective pilot study was based at the Tygerberg Children’s Hospital Gastroenterology Unit, a tertiary referral unit in Cape Town, South Africa. Written informed consent was obtained from the legal guardian and ethical approval was obtained from Stellenbosch University’s Human Research Ethics Committee. Ten children between the ages 6-59 months admitted to the Gastroenterology Unit and classified as having kwashiorkor or marasmic kwashiorkor were included. Children were excluded if they were known with pre-existing renal or endocrine disease involving phosphate, magnesium or calcium metabolism. Additionally patients transferred from referring hospitals who had already initiated a refeeding and treatment regimen, any patient with a haemoglobin of ≤6g/dl on admission or any child known to be HIV positive were also excluded from the study. Methods Biochemical and anthropometric variables were monitored during the course of treatment and refeeding. Management of the patients was standardised as per the Tygerberg Children’s Hospitals protocol for refeeding in severe acute malnutrition, which is in accordance with the WHO 10 step protocol. Treatment of hypophosphatemia included oral administration of 75-100 mg/kg/day of 0.8g Na2HPO4 + 0.2g KH2PO4 + 10 ml H2O providing a solution of 100 mg PO4/ml (7.8 mmol of phosphate per 10 mls solution). If patients were unable to tolerate oral feeds intravenous KPO4 was administered at 1 mmol/kg/day of phosphate. Results On admission 70% of children were assessed as severely underweight for age (median WAZ: -2.77, IQR: -5.07; -1.10) and 60% as stunted (median HAZ: -2.52, IQR: -5.23; -1.14) based on the WHO Z-score classification. All children were oedematous. Serum phosphate levels fell within the reference range for age (median: 1.3 mmol/l, IQR: 0.9; 1.4) and decreased to a nadir on day 7 (median: 1.15 mmol/l, IQR: 0.82; 1.5) despite routine phosphate supplementation. Low serum ionised calcium concentration at baseline (median: 1.8, IQR: 1.6; 1.88) reached a nadir at day 3 of treatment (median: 1.71, IQR: 1.53; 1.98), associated with a peak in PTH secretion on day 7 (median: 11.35, IQR: 9.1; 13.6), and an increased urinary phosphate (median: 3.85 IQR: 0.9; 37.85) on day 14. Renal threshold for phosphate reabsorption remained low throughout the course of refeeding and none of the patients developed biochemical evidence of refeeding syndrome. A significant positive correlation between ionised calcium and phosphate (p=0.004) was determined when calculating the Spearman Rank co-efficient; indicating that low serum ionised calcium concentration contributed to hypophosphatemia. This finding was confirmed by appropriate physiologic response to ionised serum hypocalcaemia by the parathyroid hormone axis. Although a positive correlation between urinary and serum phosphate; and a negative correlation between urinary phosphate and serum calcium were observed as expected; these were not found to be statistically significant, possibly due to the limited sample size and missing variables. However, a significant negative correlation (p=0.0012) was demonstrated between ionised calcium levels and PCT; this finding is previously undescribed in the setting of SAM. Conclusion This study demonstrated that in children recovering from SAM, low serum ionised calcium levels are a potential driver for phosphaturia in the face of hypophosphatemia. This is mediated via an appropriate PTH response. Further investigation of calcium supplementation and the contribution of vitamin D to phosphate homeostasis in SAM should be undertaken.
- ItemAge-disparity, sexual connectedness and HIV infection in disadvantaged communities around Cape Town, South Africa: A study protocol(BioMed Central Ltd, 2011) Delva, Wim; Beauclair, Roxanne; Welte, Alex; Vansteelandt, Stijn; Hens, Niel; Aerts, Marc; Du Toit, Elizabeth; Beyers, Nulda; Temmerman, MarleenAbstract: Background Crucial connections between sexual network structure and the distribution of HIV remain inadequately understood, especially in regard to the role of concurrency and age disparity in relationships, and how these network characteristics correlate with each other and other risk factors. Social desirability bias and inaccurate recall are obstacles to obtaining valid, detailed information about sexual behaviour and relationship histories. Therefore, this study aims to use novel research methods in order to determine whether HIV status is associated with age-disparity and sexual connectedness as well as establish the primary behavioural and socio-demographic predictors of the egocentric and community sexual network structures. Method/Design We will conduct a cross-sectional survey that uses a questionnaire exploring one-year sexual histories, with a focus on timing and age disparity of relationships, as well as other risk factors such as unprotected intercourse and the use of alcohol and recreational drugs. The questionnaire will be administered in a safe and confidential mobile interview space, using audio computer-assisted self-interview (ACASI) technology on touch screen computers. The ACASI features a choice of languages and visual feedback of temporal information. The survey will be administered in three peri-urban disadvantaged communities in the greater Cape Town area with a high burden of HIV. The study communities participated in a previous TB/HIV study, from which HIV test results will be anonymously linked to the survey dataset. Statistical analyses of the data will include descriptive statistics, linear mixed-effects models for the inter- and intra-subject variability in the age difference between sexual partners, survival analysis for correlated event times to model concurrency patterns, and logistic regression for association of HIV status with age disparity and sexual connectedness. Discussion This study design is intended to facilitate more accurate recall of sensitive sexual history data and has the potential to provide substantial insights into the relationship between key sexual network attributes and additional risk factors for HIV infection. This will help to inform the design of context-specific HIV prevention programmes.
- ItemAggressive desmoid fibromatosis : first case in a Rwandan child(Health & Medical Publishing Group, 2013-08-30) Kanyamuhunga, Aimable; McCall, Natalie; Tuyisenge, Lisine; Mumena, Crispus; Stefan, Daniela CristinaDesmoid tumours are a rare group of locally aggressive, non-malignant tumours of fibroblastic origin that can result in significant morbidity due to local invasion. Facial involvement in children with aggressive fibromatosis is uncommon. We present the case of a 14-month-old Rwandan child with an aggressive desmoid tumour involving the left mid-facial region. The patient presented with severe stertor due to massive nasal obstruction. After intensive supportive care the diagnosis was confirmed histopathologically. Treatment consisted of eight courses of chemotherapy with vincristine, actinomycin-D and cyclophosphamide followed by surgical removal of the remaining mass. The outcome was impressive and encouraging.
- ItemAminoglycoside-induced hearing loss in HIV-positive and HIV-negtive multidrug-resistant tuberculosis patients(Health and Medical Publishing Group (HMPG), 2012-06) Harris, Tashneem; Bardien, Soraya; Schaaf, H. Simon; Petersen, Lucretia; De Jong, Greetje; Fagan, Johannes J.Background. Ototoxicity following aminoglycoside treatment for multidrug-resistant tuberculosis (MDR-TB), is a significant problem. This study documents the incidence of ototoxicity in HIVpositive and HIV-negative patients with MDR-TB and presents clinical guidelines relating to ototoxicity. Methods. A prospective cohort study of 153 MDR-TB patients with normal hearing and middle ear status at baseline controlling for 6 mitochondrial mutations associated with aminoglycosiderelated ototoxicity, at Brooklyn Chest Hospital in Cape Town. Pure tone audiometry was performed monthly for 3 months to determine hearing loss. HIV status was recorded, as was the presence of 6 mutations in the MT-RNR1 gene. Results. Fifty-seven per cent developed high-frequency hearing loss. HIV-positive patients (70%) were more likely to develop hearing loss than HIV-negative patients (42%). Of 115 patients who were genetically screened, none had MT-RNR1 mutations. Conclusion. Ototoxic hearing loss is common in MDR-TB patients treated with aminoglycosides. HIV-positive patients are at increased risk of ototoxicity. Auditory monitoring and auditory rehabilitation should be an integral part of the package of care of MDR-TB patients.
- ItemAnalysis of care received by very-low-birthweight neonates at Worcester Provincial Hospital in 2018 after implementation of the Western Cape Provincial Peri-viability Decision Support Framework(Stellenbosch : Stellenbosch University, 2022-08) van der Merwe, Carine; Slogrove, Amy; Engelbrecht, Arnold; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.ENGLISH ABSTRACT: Background: A significant proportion of very-low-birthweight (VLBW; <1500g) infants are born at regional hospitals in South Africa (SA) and little is known regarding their care and outcomes. Since 2017, clinicians at regional hospitals throughout the Western Cape (WC) have utilized the WC Department of Health Periviability Decision Support Framework to guide care of VLBW infants. Objectives: To describe care of VLBW infants at Worcester Provincial Hospital (WPH) in 2018, compared to recommendations in the Framework and to secondarily compare differences in shortterm outcomes of VLBW infants managed before (2016) and after (2018) the implementation of these guidelines. Methods: A retrospective cohort study was conducted of all live-born VLBW infants ≤7 days managed at WPH, in 2016 and 2018. Information related to neonatal care was collected from medical records of patients born in 2018 only, and compared with Framework recommendations according to birthweight categories (500-799g; 800-999g; 1000-1499g). Information regarding mortality at discharge and at age 12 months, readmission before age 12 months, and length of neonatal stay was captured for all included neonates. Results were reported using frequencies, percentages, and proportions with corresponding 95% confidence intervals. Results: In total 227 infants were included, of which 115 were born in 2018 and included in the primary objective analysis. Infant and maternal characteristics were similar for the 2016 and 2018 cohorts. Complete framework adherence was achieved in 54% (n=90) of infants 1000-1499g, 42% (n=12) of infants 800-999g, and no infants of 500-799g were managed with complete adherence. Adherence to ≥80% of recommendations was achieved in 69% of infants. For the secondary objectives, survival to discharge (73.2% in 2016 vs 71.9% in 2018) and 1 year (70.5% in 2016 vs 70.4% in 2018) did not change significantly after Framework implementation. Clinically meaningful reductions in neonatal readmissions (30.6% in 2016 vs 23.5% in 2018) and length of stay (33 days in 2016 vs 28 days in 2018) were observed from 2016 to 2018. Conclusions: The majority of VLBW infants at WPH in 2018 were managed with ≥80% adherence to the Framework, but considerable differences in adherence were noted by birthweight categories. A clinically important decreased length of neonatal stay and readmission were observed postimplementation; this in combination with no increase in mortality represents a potential gain for a resource-restricted healthcare system.
- ItemAnd therapeutic outcomes lopinavir-ritonavir and a rifampicin containing anti-tuberculosis pharmacokinetics in children with tuberculosis/hiv co-infection treated with regimen(Stellenbosch : Stellenbosch University, 2019-10-15) Rabie, Helena; Cotton, Mark F.; Schaaf, Hendrik Simon; Gie, Robert Peter; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.ENGLISH ABSTRACT: Background Despite the scale-up of the prevention of mother to child transmission of HIV, an estimated 240,000 children were infected in 2013. Currently, The Joint United Nations Programme on HIV and AIDS (UNAIDS) estimates that 110,000 to 260,000 children less than 14 years of age are newly infected annually. Tuberculosis remains an important cause of morbidity and mortality in HIV co-infected children. The overlapping epidemiology of tuberculosis and HIV in sub-Saharan Africa is well known. Despite reductions in incident tuberculosis cases brought about by both the general roll out of antiretroviral therapy (ART) and the improvement of personal health of HIVpositive children, HIV-positive children remain at high risk for tuberculosis. Currently the World Health Organization (WHO) recommends rifampicin containing fixed-dose combinations for treatment of tuberculosis. Rifampicin induces its own metabolism and concentrations are affected by SLCO1B1CT (rs4149032) polymorphism. Rifampicin is well known to cause significant drug-drug interactions through activation of the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This activation causes significant drug interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors. In addition, SLCO1B1 521 TC (rs4149056) and CYP3A5 polymorphisms may affect lopinavir exposures through altering uptake and metabolism. Abacavir, together with the protease inhibitor lopinavir co-formulated with the pharmacokinetic enhancing protease inhibitor, ritonavir, is a preferred first-line medication for young children with HIV. Rifampicin causes up to 90% reduction in lopinavir exposure, but there are no data on its effect on abacavir in children. Understanding these interactions is essential to ensure effective co-treatment that will suppress HIV replication during co-treatment. For co-formulated lopinavir with ritonavir in a 4:1 ratio, achieving a morning trough concentration (Ctrough) of ≥1mg/L is associated with acceptable viral load outcomes. Doubling the dose of co-formulated lopinavir-ritonavir-4:1 does not consistently achieve this target in children, but limited data suggested that adding ritonavir to achieve a 1:1 ratio of lopinavir-ritonavir (LPV/RTV-1:1) is successful. Furthermore, modelling data suggested that an 8-hourly adjusted dose may achieve this lopinavir trough concentration target, but there was no pharmacokinetic data to this effect. We undertook studies to evaluate two strategies to adjust medication in co-treated children and performed pharmacokinetic evaluation and safety evaluations during these studies and assessed virological outcomes in the larger study. We also studied the pharmacokinetic profile of abacavir during rifampicin containing first-line tuberculosis therapy. Methods To study the lopinavir morning Ctrough and the abacavir area under the curve from 0- 12 hours (AUC0-12) during LPV/RTV-1:1 we prospectively enrolled HIV-positive children with tuberculosis requiring co-treatment with rifampicin and oral solution lopinavir-ritonavir-4:1. Children weighing 3 kg to 15 kg and a post-conception age more than 42 weeks were included into a prospective, multicentre, open-label, nonrandomized study. Children received lopinavir-ritonavir-4:1 with additional ritonavir to achieve a 1:1 ratio. Weight-banded doses of anti-tuberculosis and antiretroviral medications were used. Three intensive pharmacokinetic evaluations were done: the first in the intensive phase of tuberculosis treatment, the second in the last month of tuberculosis treatment and the third evaluation two weeks after completing tuberculosis treatment. We compared a model-based morning Ctrough of lopinavir at the second assessment and the third assessment and tested for non-inferiority, using a non-inferiority margin of 10%. We also assessed model-based abacavir AUC0-12 during LPV/RTV-1:1 superboosting and thereafter. Safety, tolerability and virological outcomes were assessed through special investigations, including hepatic enzymes, electrocardiogram, viral load tests and resistant tests as well as questionnaires. In the second study, children were switched from standard of care (super-boosted lopinavir-ritonavir 1:1) to receive 2 weeks of adjusted dose 3 times daily lopinavirritonavir 4:1. After 2 weeks an intensive pharmacokinetic evaluation was performed and the patient switched back to standard of care ART. We determined the number of children with a morning Ctrough of lopinavir ≥1mg/L. Safety was assessed by measuring hepatic enzymes. Results For the first strategy (LPV/RTV-1:1) 96 children with a median age of 18.2 months enrolled into a non-inferiority study of super-boosting lopinavir-ritonavir-4:1 to achieve a 1:1 ratio. Of these 96 children, 80 (83%) completed all three pharmacokinetic evaluations. The model-based lopinavir morning Ctrough on super-boosted lopinavir ritonavir 4:1 with additional ritonavir to achieve a 1:1 ratio whilst receiving rifampicinbased tuberculosis treatment was non-inferior to the model-based morning Ctrough in children on lopinavir-ritonavir-4:1 after the end of tuberculosis therapy and superboosting. The model-predicted percentage of morning Ctrough less than 1.0 mg/L after tuberculosis treatment without super-boosting was 8·8% (95% confidence interval [CI] 0·6–19·8), versus 7·6% (95% CI 0·4–16·2) during super-boosting and tuberculosis treatment. At the non-inferiority margin of 10%, this difference of –1·1% (95% CI –6·9 to 3·2) met the criterion for non-inferiority. This strategy was safe and the viral load outcomes were acceptable: children who failed to suppress HIV did not develop resistance. Caretakers reported poor palatability and tolerability of both lopinavirritonavir-4:1 oral solution and ritonavir oral solution. For the second strategy (8-hourly adjusted dosing) 11 children were enrolled into the study assessing adjusted-dose 8-hourly lopinavir-ritonavir 4:1. Children were divided into two weight bands: 5 (45%) were 10–13.9 kg and received 20–24 mg/kg/dose, and 6 (55%) children weighed 6–9.9 kg and received 20–23 mg/kg/dose of lopinavir. Seven children (63.6%) met the suggested morning Ctrough target. Children with a lopinavir mg/kg dose below the median of 21.5mg/kg/dose were more likely to have a morning Ctrough below 1 mg/L (p=0.02). There was a strong correlation between lopinavir and ritonavir concentrations. To model the AUC0-12 of abacavir we included 85 children at PK1, 74 at children at PK2 and 72 children at PK3 on abacavir and in whom pharmacokinetic information was available. Children were participating in the non-inferiority study of super-boosted lopinavir-ritonavir-4:1 to achieve a 1:1 ratio. Abacavir pharmacokinetics was described by a two-compartment model with first-order elimination and transit compartment absorption. Clearance was predicted to reach half its mature value at around 2 months after birth and to be fully mature by approximately 2 years of age. During coadministration of rifampicin and super-boosting with ritonavir, a 36% decrease in bioavailability (and AUC0-12) was found. Conclusions Super-boosting lopinavir-ritonavir-4:1 with ritonavir to a 1:1 ratio during rifampicin containing tuberculosis treatment is non-inferior to lopinavir-ritonavir-4:1 without rifampicin. It is also safe and effective but it is poorly tolerated and has poor palatability. Adjusted 8-hourly dosing requires further study. During super-boosting of lopinavir-ritonavir while on rifampicin containing tuberculosis treatment, there is a drug interaction causing a 36% reduction in abacavir AUC0-12
- ItemAnnual risk of tuberculous infection using different methods in communities with a high prevalence of TB and HIV in Zambia and South Africa(Public Library of Science (PLOS), 2009-11) Shanaube, Kwame; Sisminidis, Charalambos; Ayles, Helen; Beyers, Nulda; Schaap, Ab; Lawrence, Katherine-Anne; Barker, Annie; Godfrey-Faussett, PeterBackground: The annual risk of tuberculous infection (ARTI) is a key epidemiological indicator of the extent of transmission in a community. Several methods have been suggested to estimate the prevalence of tuberculous infection using tuberculin skin test data. This paper explores the implications of using different methods to estimate prevalence of infection and ARTI. The effect of BCG vaccination on these estimates is also investigated. Methodology/Principal Findings: Tuberculin surveys among school children in 16 communities in Zambia and 8 in South Africa (SA) were performed in 2005, as part of baseline data collection and for randomisation purposes of the ZAMSTAR study. Infection prevalence and ARTI estimates were calculated using five methods: different cut-offs with or without adjustments for sensitivity, the mirror method, and mixture analysis. A total of 49,835 children were registered for the surveys, of which 25,048 (50%) had skin tests done and 22,563 (90%) of those tested were read. Infection prevalence was higher in the combined SA than Zambian communities. The mirror method resulted in the least difference of 7.8%, whereas that estimated by the cut-off methods varied from 12.2% to 17.3%. The ARTI in the Zambian and SA communities was between 0.8% and 2.8% and 2.5% and 4.2% respectively, depending on the method used. In the SA communities, the ARTI was higher among the younger children. BCG vaccination had little effect on these estimates. Conclusions/Significance: ARTI estimates are dependent on the calculation method used. All methods agreed that there were substantial differences in infection prevalence across the communities, with higher rates in SA. Although TB notification rates have increased over the past decades, the difference in cumulative exposure between younger and older children is less dramatic and a rise in risk of infection in parallel with the estimated incidence of active tuberculosis cannot be excluded. © 2009 Shanaube et al.
- ItemAnother phenocopy for chondrodysplasia punctata in addition to warfarin embryopathy?(HMPG, 1978) Gericke G.S.; van der Walt A.; de Jong G.[No abstract available]
- ItemAnti-Group B Streptococcus antibody in infants born to mothers with human immunodeficiency virus (HIV) infection(Elsevier, 2015-01-29) Le Doare, Kirsty; Allen, Lauren; Kampmann, Beate; Heath, Paul Trafford; Taylor, Stephen; Hesseling, Anneke C.; Gorringe, Andrew; Jones, Christine ElizabethBackground: HIV-exposed uninfected infants have increased infection risk and mortality compared to HIV-unexposed infants. HIV-exposed infants may be at increased risk of invasive GBS disease due to reduced maternal antibody against GBS. Methods: We quantified antibodies that bind to the surface of whole Group B Streptococcus (GBS) of serotypes Ia, Ib, II, III and V using novel flow cytometry assays in South African HIV-infected and non-infected mothers and their uninfected infants. Antibody-mediated complement C3b/iC3b deposition onto GBS of these serotypes was also quantified by a novel flow cytometry assay. Results: Geometric mean concentration (GMC) of both surface-binding anti-GBS antibody and antibody-mediated complement deposition onto GBS were reduced in HIV-infected women (n = 46) compared to HIV-uninfected women (n = 58) for ST1a (surface-binding: 19.3 vs 29.3; p = 0.003; complement deposition: 2.9 vs 5.3 SU/mL; p = 0.003), STIb (24.9 vs 47.6; p = 0.003; 2.6 vs 4.9 SU/mL; p = 0.003), STII (19.8 vs 50.0; p = 0.001; 3.1 vs 6.2 SU/mL; p = 0.001), STIII (27.8 vs 60.1; p = 0.001; 2.8 vs 5.3 SU/mL; p = 0.001) and STV (121.9 vs 185.6 SU/mL; p < 0.001) and in their infants for STIa (complement deposition 9.4 vs 27.0 SU/mL; p = 0.02), STIb (13.4 vs 24.5 SU/mL; p = 0.02), STII (14.6 vs 42.7 SU/mL; p = 0.03), STIII (26.6 vs 62.7 SU/mL; p = 0.03) and STV (90.4 vs 165.8 SU/mL; p = 0.04). Median transplacental transfer of antibody from HIV-infected women to their infants was reduced compared to HIV-uninfected women for GBS serotypes II (0.42 [IQR 0.22–0.59] vs 1.0 SU/mL [0.42–1.66]; p < 0.001), III (0.54 [0.31–1.03] vs 0.95 SU/mL [0.42–3.05], p = 0.05) and V (0.51 [0.28–0.79] vs 0.75 SU/mL [0.26–2.9], p = 0.04). The differences between infants remained significant at 16 weeks of age. Conclusions: Maternal HIV infection was associated with lower anti-GBS surface binding antibody concentration and antibody-mediated C3b/iC3b deposition onto GBS bacteria of serotypes Ia, Ib, II, III and V. This may render these infants more susceptible to early and late onset GBS disease.
- ItemAntibiotic use profile in a South African paediatric intensive care unit: A Prospective cohort description(Stellenbosch : Stellenbosch University, 2022-10) Gobetz, Charle; Rabie, Helena; Parker, Noor; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.ENGLISH ABSTRACT: Background Antibiotic overuse and emerging bacterial resistance is a growing threat to global health and an important point of intervention to protect future effectiveness of antibiotics. Critically ill children who are admitted to an intensive care unit are generally started on broad-spectrum antibiotics as this is necessary within the first hour of identification of sepsis to improve survival. In describing the indications and patterns of antibiotic use in our PICU we aim to reveal opportunities to improve antibiotic stewardship practices and contribute to overcoming a growing problem of antimicrobial resistance. Objectives To comprehensively describe antibiotic utilization in the PICU at Tygerberg Hospital and to assess the appropriateness of antibiotic prescribing. Methods We conducted a prospective observational antibiotic utilization study which enrolled 150 children between 1 January 2020 and 23 March 2020. Results There were 133 children admitted to PICU representing 150 admission episodes. The median age of the children at admission were 20.6 months (IQR 4.4 – 64.0). Hundred and five (70%) children had a medical reason for admission with sepsis being the most common diagnosis among the youngest age groups. There was a significant difference in reason for admission between the different age groups (p=0.007) with surgical reasons becoming more likely with increasing age. Of 150 admissions 70 (46.6%) were noted to have one or more comorbid conditions with chronic lung disease and prematurity being the most common. Only 93 (66.9%) of admissions had a weight for age z-score (WAZ) in the -2 to +2 z-score range. A substantial number of admissions (24.5%, n=34) had a WAZ of <-3. In 121 (80.6%) admissions patients received antibiotics in the week prior to PICU admission. There were also 7 (5.8%) instances of carbapenems given prior to PICU admission. Twenty-five admissions (16.7%) did not receive any antibiotic. The total antibiotic use was 1256 days of therapy (DOT) /1000 patient days. Most of the antibiotic prescriptions (79.6%, n=535) were classified as empiric prescriptions. Meropenem was the antibiotic most frequently started in PICU and used for the greatest total number of days (n=140). Of the 125 admissions where antibiotics were used 66 (52.8%) were appropriate for all prescriptions and all revisions to prescriptions. We found a blood culture pathogen yield of 11.2% and a contamination rate of 7.5%. Conclusion We confirmed a high rate of empiric antibiotic utilization with evidence of overuse and inappropriate escalation decisions. Inappropriate use was mostly related to incorrect empirical choices, and prolonged courses of antibiotics.
- ItemAntiretroviral therapy for the management of HIV in children(Health & Medical Publishing Group, 2014-12) Frigati, L.; Cotton, Mark F.; Rabie, H.Since 2004, when antiretroviral therapy (ART) was first available to children through the National Department of Health, there has been significant progress in preventing and treating paediatric HIV. Large cohort studies and prospective trials confirmed that young children require early diagnosis with rapid access to ART regardless of CD4+ lymphocyte count. Studies also confirmed the importance of ritonavir-boosted protease inhibitors during therapy, regardless of prior nevirapine exposure. As prevention strengthens and the paediatric population ages, the goal posts are shifting towards even earlier diagnosis, targeting newborn infants on the first day of life and also the perinatally infected adolescent. There is an increasing focus on the long-term health, social, developmental and scholastic outcomes of HIV-infected children. Clinicians require new skills to assist children with transition into adulthood. In this article we focus on the care of infants and children.
- ItemAntiretroviral therapy in children - increased benefit from increased complexity(Health & Medical Publishing Group, 2000-10) Cotton, Mark F.Antiretroviral therapy (ART) started as monotherapy with significant short-term gains. With the advent of newer drugs management has become more complex, but with significant gains in quality and quantity of life. The evolution of ART in children lags behind that of adults for many reasons. These include an unwillingness to use new medications in children before efficacy has been established and also difficulty in developing suitable formulations for children. ART has progressed from monotherapy to dual, triple and even quadruple therapy, stimulated by insights into the rapidity of viral replication, development of resistance, and availability of new agents. The most pressing concern with ART is its lack of accessibility to the majority of patients that need it. Other important issues are how and when to use it in ways that promote durability of response but avoid unnecessary use. Most information is derived from studies with relatively short periods of follow-up. The long-term durability of therapy is not known, but with development of new agents should be sustained.
- ItemApproach to headaches in children(Health & Medical Publishing Group, 2011) Solomons, Regan; Schoeman, Johan; Van Toorn, RonaldHeadache is a common problem in childhood – up to 25% of schoolchildren suffer from chronic, recurrent headaches. Although primary headaches are far more common than those with a secondary cause, it is the latter that result in the most anxiety for families.1 A logical approach to investigating and managing headaches is needed.
- ItemAssessing the impact of multidrug-resistant tuberculosis in children : an exploratory qualitative study(BioMed Central, 2014-08) Franck, Caroline; Seddon, James A.; Hesseling, Anneke C.; Schaaf, H. Simon; Skinner, Donald; Reynolds, LucyBackground: While the prevalence of multidrug-resistant (MDR) tuberculosis (TB) is high among children in the Western Cape of South Africa, the psychosocial implications of treatment for children with MDR-TB remain poorly understood. We sought to explore how MDR-TB and its treatment impact children on an individual, familial, and social level. Methods: Semi-structured interviews were conducted with 20 children and caregivers purposively sampled from a prospective clinical cohort of children. The sample was stratified by age at the start of treatment (children >10 years, and 5-10 years). Caregiver proxy interviews were conducted with younger children, supplemented with child interviews; older children were interviewed directly, supplemented with caregiver proxy interviews. Data were analysed using grounded theory. Results: Findings revealed pill volume and adverse effects produced significant physical, psychological and academic disturbances in children. Adverse effects related to the medication were important obstacles to treatment adherence. While there appear to be no long-lasting effects in younger children, a few older children showed evidence of persisting internalised stigma. Caregivers suffered important treatment-related financial and psychological costs. Community support, notably through the continued involvement of children in strong social networks, promoted resilience among children and their families. Conclusions: We found that the current treatment regimen for childhood MDR-TB has significant psychological, academic, and financial impacts on children and their families. There is a need for psychosocial support of children and caregivers to mitigate the negative effects of community stigma, and to manage the stressors associated with chronic illness.