A Retrospective Study Evaluating Neonatal Vancomycin Loading Doses to Achieve a Therapeutic Target.

BACKGROUND: Vancomycin is a glycopeptide antibiotic that has been used to treat hospital-acquired gram-positive infections for more than 5 decades. However, the literature is divided regarding the therapeutic advantages of vancomycin loading doses in neonates. OBJECTIVES: This study aimed to investigate the effect of vancomycin loading doses on therapeutic target attainment in neonates with sepsis. METHODS: A retrospective cohort study was conducted to compare the vancomycin target attainment (area under the curve 0-24 hours/minimum inhibitory concentration ≥400) in neonates before and after the 2019 change in vancomycin prescription guidelines at a neonatal unit in Cape Town, South Africa. As the standard of care, Bayesian modelling software was used to compute the area under the curve from the trough concentrations. RESULTS: Two hundred ten neonates were included. Multivariate regression analysis showed a 2-fold increase in the odds of target attainment among neonates receiving a loading dose of vancomycin. Early target attainment (within 8-12 hours of treatment initiation) was significantly higher in the loading dose group compared with the no loading dose group [97/105 (92.4%) versus 64/105 (61.0%); P < 0.001]. However, the overall proportion of neonates achieving target attainment at 24 hours was similar between groups [73/105 (69.5%) in the loading dose group versus 62/105 (59.0%) in the no loading dose group; P = 0.110]. The nephrotoxicity rates were low [2/105 (1.9%) in the loading dose group and 2/105 (1.9%) in the no loading dose group]. CONCLUSIONS: The addition of a vancomycin loading dose to neonates may facilitate early therapeutic target attainment.

The Ocular Penetration and Intraocular Pressure Lowering Effect of Topical Acetaminophen in the New Zealand White Rabbit.

Purpose: Emerging data suggest that acetaminophen lowers intraocular pressure (IOP) and has the potential to be repurposed as pharmacotherapy to treat open-angle glaucoma. However, pharmacokinetic data are lacking. This study aims to describe the pharmacokinetics of topical acetaminophen and its metabolite [N-arachidonoylaminophenol (AM404)] when administered individually and in combination, and to determine its effect on IOP in the ocular normotensive adult New Zealand White Rabbit (NZWR). Methods: A randomized control trial was conducted using topical 1% acetaminophen and 1% AM404. The study was divided into two sub-studies using both paired-eye and two-eye designs. Results: The mean [95% confidence interval of the mean (95% CI)] concentration of acetaminophen detected in the aqueous humor (AH) was 4.09 ppm (3.18-5.00) at 2 h and 0.92 ppm (0.60-1.24) at 4 h after an immediate dose of topical acetaminophen. The integral IOP, defined as the integral of IOP change from baseline over time, was -5.1 mmHg⋅h (95% CI: -10 to 0.41) for control,-7.5 mmHg⋅h (95% CI: -14 to -1.1) for half-hourly acetaminophen, and -4.4 mmHg⋅h (95% CI: -14 to 5.5) for hourly acetaminophen over a 4-h period. When comparing topical acetaminophen with AM404 dosed half-hourly over a 4-h period, the integral IOP was -2.3 mmHg⋅h (95% CI: -5.9 to 1.3) for control,-2.0 mmHg⋅h (95% CI: -5.6 to 1.7) for AM404, -1.7 mmHg⋅h (95% CI: -4.5 to 1.2) for acetaminophen, and -3.2 mmHg⋅h (95% CI: -5.4 to -0.96) for acetaminophen/AM404 combined. Conclusions: Acetaminophen, but not its metabolite AM404, penetrated the multilayered cornea via passive diffusion in a dose-dependent fashion. There was a nonsignificant tendency to cause a lowering of IOP over the 4-h dosing period with higher AH concentrations of acetaminophen. Topical AM404 did not show a significant IOP-lowering effect.

Clinical characteristics associated with mortality of COVID-19 patients admitted to an intensive care unit of a tertiary hospital in South Africa.

BACKGROUND: Over 130 million people have been diagnosed with Coronavirus disease 2019 (COVID-19), and more than one million fatalities have been reported worldwide. South Africa is unique in having a quadruple disease burden of type 2 diabetes, hypertension, human immunodeficiency virus (HIV) and tuberculosis, making COVID-19-related mortality of particular interest in the country. The aim of this study was to investigate the clinical characteristics and associated mortality of COVID-19 patients admitted to an intensive care unit (ICU) in a South African setting. METHODS AND FINDINGS: We performed a prospective observational study of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection admitted to the ICU of a South African tertiary hospital in Cape Town. The mortality and discharge rates were the primary outcomes. Demographic, clinical and laboratory data were analysed, and multivariable robust Poisson regression model was used to identify risk factors for mortality. Furthermore, Cox proportional hazards regression model was performed to assess the association between time to death and the predictor variables. Factors associated with death (time to death) at p-value < 0.05 were considered statistically significant. Of the 402 patients admitted to the ICU, 250 (62%) died, and another 12 (3%) died in the hospital after being discharged from the ICU. The median age of the study population was 54.1 years (IQR: 46.0-61.6). The mortality rate among those who were intubated was significantly higher at 201/221 (91%). After adjusting for confounding, multivariable robust Poisson regression analysis revealed that age more than 48 years, requiring invasive mechanical ventilation, HIV status, procalcitonin (PCT), Troponin T, Aspartate Aminotransferase (AST), and a low pH on admission all significantly predicted mortality. Three main risk factors predictive of mortality were identified in the analysis using Cox regression Cox proportional hazards regression model. HIV positive status, myalgia, and intubated in the ICU were identified as independent prognostic factors. CONCLUSIONS: In this study, the mortality rate in COVID-19 patients admitted to the ICU was high. Older age, the need for invasive mechanical ventilation, HIV status, and metabolic acidosis were found to be significant predictors of mortality in patients admitted to the ICU.

Concentrations of Efavirenz, Tenofovir, and Emtricitabine in Obesity: A Cross-Sectional Study.

BACKGROUND: Obesity is increasing worldwide including in people living with HIV (PLWH). Antiretroviral pharmacokinetic data in obesity are limited. OBJECTIVES: To measure antiretroviral drug concentrations in obese and nonobese PLWH treated with the fixed-dose combination of efavirenz-tenofovir-emtricitabine. To determine pharmacokinetic differences across indicators of obesity and their associated immunovirological outcomes. METHODS: We conducted a cross-sectional sample analysis of 2 cohort studies. We measured mid-dose efavirenz, 8-hydroxy-efavirenz, tenofovir, and emtricitabine concentrations. Antiretroviral drug concentrations were analyzed by body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR). RESULTS: We performed a study of 213 participants: General obesity was detected in 20.4% using BMI and abdominal obesity in 53.6% using WC and 62.4% using WHR, respectively. The median concentrations of all antiretroviral drugs were lower among obese participants determined by BMI and WC, with efavirenz showing greater differences than tenofovir or emtricitabine. For BMI, results were most striking for efavirenz (1752.3 vs 2342.9 ng/mL, P = 0.002) with lower concentrations in obese participants. Using WC, efavirenz (1845.8 vs 2571.2 ng/mL, P < 0.001), tenofovir (65.8 vs 73.2 ng/mL, P = 0.036), and emtricitabine (159.5 vs 221.0 ng/mL, P = 0.005) concentrations were lower in obese participants. Eight-hydroxyefavirenz concentrations were similar in nonobese and obese participants for WC. Using WHR, the concentrations of all antiretroviral drugs were lower in the obese population, most strikingly for emtricitabine (173.5 vs 229.0 ng/mL, P = 0.015). There were no immunovirological associations. CONCLUSION: We found lower antiretroviral concentrations in all obese groups, most strikingly in participants with abdominal obesity determined by WC. Lower drug concentrations had no immunovirological associations.

Prevalence and Characteristics of HIV-Associated Stroke in a Tertiary Hospital Setting in South Africa.

BACKGROUND AND OBJECTIVES: Antiretroviral treatment (ART) era HIV-associated stroke data from sub-Saharan Africa are limited. We determined the prevalence of HIV in patients presenting with acute symptomatic stroke and compared risk factors, clinical characteristics, and brain imaging with age-matched stroke patients without HIV. METHODS: We conducted a retrospective study of adults presenting with any type of stroke to Tygerberg Hospital in a 12-month period. Patients living with HIV (PLWH) and HIV-uninfected (HIV-) patients were matched based on age group (1:2 ratio). Patients were identified by keyword search, while HIV status was ascertained from laboratory data. Clinical and imaging data were extracted from medical records. RESULTS: Among 884 patients presenting with acute strokes, the minimum prevalence of HIV infection was 9.3% (95% CI: 7.4%-11.2%), with 496 patients (56.1%) with negative HIV status and 306 patients with unknown HIV status (34.6%). The mean age at presentation in PLWH was 46 (±11) years compared with 55 (±14) years in HIV- patients (p < 0.001). Smoking was less prevalent in PLWH with an adjusted relative risk ratio of RR = 0.58 (95% CI: 0.39-0.86). Concurrent infection was more prevalent in PLWH (25.6% vs 4.9%, p ≤ 0.001) with an adjusted relative risk ratio of RR = 2.07 (95% CI: 1.49-2.84), largely in patients with a CD4 count <200 cells/µL. PLWH with higher CD4 counts (≥200 cells/µL, 51.3%) had more traditional risk factors and less concurrent infection. Among PLWH, 68.3% were on ART, and 39.3% of them had been started or restarted on ART within the past 6 months. Basal ganglia infarcts (35.6% vs 18.3%, p = 0.014) and multiple vascular territory involvement (25.4% vs 7.7%, p = 0.002) were more common in PLWH. Clinical presentation, ischemic stroke type, and in-hospital outcomes did not differ between the groups. DISCUSSION: Stroke patients with HIV were younger, had less traditional cardiovascular risk factors, and more concurrent infections than patients without HIV, especially those with a lower CD4 count. Recent ART initiation or reinitiation rates were high. Significant differences in CT brain imaging findings were seen. Understanding the multifactorial mechanisms underlying increased stroke risk, including associated infections and potential ART-associated immune reconstitution, is crucial and needs further study.

Population pharmacokinetics of esomeprazole in patients with preterm preeclampsia.

Esomeprazole is a proton pump inhibitor being investigated for treatment of preeclampsia. Esomeprazole pharmacokinetics during pregnancy are unknown. We used data from 10 pregnant participants with preterm preeclampsia, and 49 non-pregnant participants to develop a population pharmacokinetic model of esomeprazole. A two-compartment model described the data well. In pregnant participants after single dose, clearance was 42.2% (14.9-61.6%) lower compared to non-pregnant, most likely due to inhibition of CYP2C19. In non-pregnant participants after repeated dosing, clearance was 54.9% (48.2-63.5%) lower in extensive metabolizers and bioavailability was 33% (10.0-52.0%) higher compared to single dosing, which could be due to autoinhibition of CYP2C19. During pregnancy, the CYP2C19 autoinhibition effect with repeated dosing is expected to lead to much lower increase in exposure compared to non-pregnant individuals, since CYP2C19 is already inhibited due to pregnancy.

Drug concentration at the site of disease in children with pulmonary tuberculosis.

BACKGROUND: Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB. OBJECTIVES: To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB. METHODS: We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions. RESULTS: Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions. CONCLUSIONS: Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.

Pharmacogenetics of the Late-Onset Efavirenz Neurotoxicity Syndrome (LENS).

BACKGROUND: The late-onset efavirenz neurotoxicity syndrome (LENS) presents as ataxia and/or encephalopathy with supratherapeutic efavirenz plasma concentrations (>4 µg/mL). Efavirenz is primarily metabolized by cytochrome P450 2B6 (CYP2B6), with CYP2A6 as an accessory pathway. We hypothesized that participants with LENS would predominantly be CYP2B6 slow metabolizers. The aim of our study was to determine the frequency of CYP2B6 slow metabolizers in participants with LENS. METHODS: Adult HIV-positive participants on efavirenz-based antiretroviral therapy presenting with LENS were prospectively enrolled. Genetic polymorphisms known to be associated with increased efavirenz plasma concentrations in CYP2B6 (rs3745274, rs28399499, rs4803419) and CYP2A6 (rs28399433) were selected and used to determine proportions of slow metabolizers. Pharmacokinetic analyses were performed using liquid chromatography-tandem mass spectrometry. Median (IQR) plasma efavirenz and 8-hydroxyefavirenz were described. RESULTS: Fifteen participants were enrolled. Thirteen (13/15) were Black-African and 13 were female. Median weight was 49.9kg with a median duration on efavirenz of 2.2 years. All 15 participants were successfully genotyped as slow CYP2B6 metabolizers, with 6 participants additionally having CYP2A6 heterozygous genotype. Thirteen were receiving the CYP2A6 enzyme inhibitor isoniazid, and all 15 were genotypic NAT2 slow or intermediate acetylators. Efavirenz plasma concentration was markedly increased at 50.5 (47.0-65.4) µg/mL; 8-hydroxyefavirenz concentration was markedly decreased at 0.10 (0.07-0.15) µg/mL. CONCLUSIONS: Our cohort provides definitive evidence that LENS is associated with the CYP2B6 slow metabolizer genotype, with a median efavirenz plasma concentration >12-fold higher than the defined upper limit of the therapeutic range. Isoniazid and low body weight are important contributors to LENS development.

Pharmacokinetics of Antimicrobials in Children with Emphasis on Challenges Faced by Low and Middle Income Countries, a Clinical Review.

Effective antimicrobial exposure is essential to treat infections and prevent antimicrobial resistance, both being major public health problems in low and middle income countries (LMIC). Delivery of drug concentrations to the target site is governed by dose and pharmacokinetic processes (absorption, distribution, metabolism and excretion). However, specific data on the pharmacokinetics of antimicrobials in children living in LMIC settings are scarce. Additionally, there are significant logistical constraints to therapeutic drug monitoring that further emphasize the importance of understanding pharmacokinetics and dosing in LMIC. Both malnutrition and diarrheal disease reduce the extent of enteral absorption. Multiple antiretrovirals and antimycobacterial agents, commonly used by children in low resource settings, have potential interactions with other antimicrobials. Hypoalbuminemia, which may be the result of malnutrition, nephrotic syndrome or liver failure, increases the unbound concentrations of protein bound drugs that may therefore be eliminated faster. Kidney function develops rapidly during the first years of life and different inflammatory processes commonly augment renal clearance in febrile children, potentially resulting in subtherapeutic drug concentrations if doses are not adapted. Using a narrative review approach, we outline the effects of growth, maturation and comorbidities on maturational and disease specific effects on pharmacokinetics in children in LMIC.

Opportunities to enhance antibiotic stewardship: colistin use and outcomes in a low-resource setting.

BACKGROUND: Colistin use is increasing with the rise in MDR Gram-negative infections globally. Effective antibiotic stewardship is essential to preserve this antibiotic of last resort. OBJECTIVES: This study investigated stewardship and safety errors related to colistin use to identify opportunities for improvement. PATIENTS AND METHODS: A prospective descriptive study involving all patients 13 years and older treated with colistin at a tertiary hospital in Cape Town, South Africa, between August 2018 and June 2019. We collected clinical, laboratory and outcome data and assessed provided treatment for stewardship and safety errors. RESULTS: We included 44 patients. Treatment errors were identified for 34 (77%) patients (median = 1), most commonly inadequate monitoring of renal function (N = 16, 32%). We also identified no rational indication for colistin (N = 9, 20%), loading dose error (N = 12, 27%); maintenance dose error (N = 10, 23%); no prior culture (N = 11, 25%); and failure to de-escalate (2 of 9) or adjust dose to changes in renal function (6 of 15). All cause in-hospital mortality was 47%. Amongst survivors, median ICU stay was 6 days and hospital stay more than 30 days. Eight (18%) patients developed renal injury or failure during treatment. Three (7%) patients in this study were found to have colistin-resistant organisms including two prior to colistin exposure. CONCLUSIONS: This study has identified opportunities to enhance colistin stewardship and improve efficacy and safety of prescription. The appearance of colistin-resistant organisms reinforces the urgent need to ensure effective and appropriate use of colistin.

Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial.

OBJECTIVE: To evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia. DESIGN: Randomised, double blind, placebo controlled trial. SETTING: Referral hospital in Cape Town, South Africa. PARTICIPANTS: 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks' gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo. INTERVENTION: 3 g of oral extended release metformin or placebo daily, in divided doses, until delivery. MAIN OUTCOME MEASURE: The primary outcome was prolongation of gestation. RESULTS: Of 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days; n=89) in the metformin arm and 10.1 (3.7-24.1; n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95; P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7; n=76) days compared with 7.9 (3.0-22.2; n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8; n=40) days compared with 4.8 (2.5-15.4; n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm. CONCLUSIONS: This trial suggests that extended release metformin can prolong gestation in women with preterm pre-eclampsia, although further trials are needed. It provides proof of concept that treatment of preterm pre-eclampsia is possible. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/.

The 12-month period prevalence and cardiac manifestations of HIV in patients with acute coronary syndrome at a tertiary hospital in Cape Town, South Africa: a retrospective cross-sectional study.

BACKGROUND: HIV-positive patients are increasingly being affected by non-communicable diseases such as coronary artery disease (CAD). Data from high-income countries (HICs) indicate that HIV-positive patients have different risk-factor profiles for acute coronary syndrome (ACS) as well as different cardiac manifestations of this syndrome compared to HIV-negative patients. There is limited data from Sub-Saharan Africa (SSA), and particularly from South Africa with the biggest HIV epidemic in the world. The objective of this study was to determine the 12-month period prevalence of HIV in patients with ACS and to compare the risk-factor profile, ACS presentation and management between HIV-positive and HIV-negative adults. METHODS: We included all patients hospitalised with ACS from 01 January to 31 December 2018 in a tertiary hospital, Tygerberg Hospital, in Cape Town, South Africa. The HIV-status of all patients was determined using routine clinical records. We performed multiple conditional logistic regression on HIV-positive and HIV-negative patients (1:3 ratio) to compare the risk factor profile, ACS presentation and management between the groups. RESULTS: Among 889 patients, 30 (3.4%) were HIV-positive (95% confidence interval (CI): 2.3-4.8). HIV-positive patients were younger, more frequently men, and had a lower prevalence of medical comorbidities and a family history of CAD. They were more likely to present with ST-elevation myocardial infarction (STEMI) [odd's ratio (OR) (95% CI): 3.12 (1.2-8.4)], and have single-vessel disease [OR (95% CI): 3.03 (1.2-8.0)]. Angiographic and echocardiographic data, as well as management, did not differ between the groups. Among HIV-positive patients, 17 (65%) were virally suppressed (HIV viral load < 200 copies/mL) with a median CD4+ count of 271 cells/mm3. The majority (20, 67%) of HIV-positive patients were receiving antiretroviral therapy at the time of the ACS. CONCLUSIONS: We found an HIV-prevalence of 3.4% (95% CI 2.3-4.8) in adults with ACS in a high endemic HIV region. HIV-positive patients were younger and more likely to present with STEMIs and single-vessel disease, but had fewer CAD risk factors, suggesting additional mechanisms for the development of ACS.

The Pharmacokinetics of Crushed Levetiracetam Tablets Administered to Neonates.

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

Pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid.

BACKGROUND: Blood-cerebrospinal fluid (CSF) barrier transporters affect the influx and efflux of drugs. The antiretrovirals tenofovir and emtricitabine may be substrates of blood-brain barrier (BBB) and blood-CSF barrier transporters, but data are limited regarding the pharmacogenetics and pharmacokinetics of their central nervous system (CNS) penetration. OBJECTIVES: We investigated genetic polymorphisms associated with CSF disposition of tenofovir and emtricitabine. METHOD: We collected paired plasma and CSF samples from 47 HIV-positive black South African adults who were virologically suppressed on efavirenz, tenofovir and emtricitabine. We considered 1846 single-nucleotide polymorphisms from seven relevant transporter genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, SLCO1B1 and ABCC4) and 782 met a linkage disequilibrium (LD)-pruning threshold. RESULTS: The geometric mean (95% confidence interval [CI]) values for tenofovir and emtricitabine CSF-to-plasma concentration ratios were 0.023 (0.021-0.026) and 0.528 (0.460-0.605), respectively. In linear regression models, the lowest p-value for association with the tenofovir CSF-to-plasma ratio was ABCB1 rs1989830 (p = 1.2 × 10-3) and for emtricitabine, it was ABCC5 rs11921035 (p = 1.4 × 10-3). None withstood correction for multiple testing. CONCLUSION: No genetic polymorphisms were associated with plasma, CSF concentrations or CSF-to-plasma ratios for either tenofovir or emtricitabine.

Clozapine-Associated Leukopenia and Agranulocytosis in Western Cape, South Africa: A 3-Year Retrospective Cohort Study.

BACKGROUND: Clozapine may cause life-threatening hematological side effects (HSEs). Hematological side effect incidence data from Sub-Saharan Africa are lacking. Furthermore, clozapine reduces cellular immunity, and it is unknown whether clozapine is a risk factor for tuberculosis or whether HIV is a risk factor for developing HSEs. We assessed the incidence of HSEs in South Africans from the Western Cape Province on clozapine, and the secondary objective was to determine the association of HIV and tuberculosis with clozapine exposure. METHODS: We conducted a 24-week retrospective descriptive study of patients initiated on clozapine between January 2015 and December 2017 using anonymized data from the Provincial Health Data Centre. A control group of patients initiated on risperidone was selected. RESULTS: We identified 23,328 patients and included 5213 who had white blood cell monitoring (n = 1047 clozapine, n = 4166 risperidone). The incidence of leukopenia in patients on clozapine was 0.38% (95% confidence interval [CI], 0.01%-0.76%) measured over a 24-week period and was 0.41% in patients on risperidone (95% CI, 0.21%-0.6%) (P = 0.91). The incidence of agranulocytosis in patients on clozapine was 0.19% (95% CI, 0.00%-0.46%) measured over a 24-week period and was 0.24% in patients on risperidone (95% CI, 0.09%-0.39%) (P = 0.266). HIV-infected patients had a 7.46 times increased risk of developing leukopenia (95% CI, 3.37-16.48; P < 0.01). Patients who developed leukopenia had a 6.24 times increased risk of contracting tuberculosis (95% CI, 1.84-21.11; P < 0.01). CONCLUSIONS: Our incidence of clozapine-induced HSEs was lower than previously reported and not significantly different compared with risperidone. HIV infection was associated with HSEs. Patients with HSEs had an increased risk of developing tuberculosis.

How COVID-19 has fundamentally changed clinical research in global health.

COVID-19 has had negative repercussions on the entire global population. Despite there being a common goal that should have unified resources and efforts, there have been an overwhelmingly large number of clinical trials that have been registered that are of questionable methodological quality. As the final paper of this Series, we discuss how the medical research community has responded to COVID-19. We recognise the incredible pressure that this pandemic has put on researchers, regulators, and policy makers, all of whom were doing their best to move quickly but safely in a time of tremendous uncertainty. However, the research community's response to the COVID-19 pandemic has prominently highlighted many fundamental issues that exist in clinical trial research under the current system and its incentive structures. The COVID-19 pandemic has not only re-emphasised the importance of well designed randomised clinical trials but also highlighted the need for large-scale clinical trials structured according to a master protocol in a coordinated and collaborative manner. There is also a need for structures and incentives to enable faster data sharing of anonymised datasets, and a need to provide similar opportunities to those in high-income countries for clinical trial research in low-resource regions where clinical trial research receives considerably less research funding.

Minimizing the impact of the triple burden of COVID-19, tuberculosis and HIV on health services in sub-Saharan Africa.

In this perspective, we discuss the impact of COVID-19 on tuberculosis (TB)/HIV health services and approaches to mitigating the growing burden of these three colliding epidemics in sub-Saharan Africa (SSA). SSA countries bear significantly high proportions of TB and HIV cases reported worldwide, compared to countries in the West. Whilst COVID-19 epidemiology appears to vary across Africa, most countries in this region have reported relatively lower-case counts compared to the West. Nevertheless, the COVID-19 pandemic has added an additional burden to already overstretched health systems in SSA, which, among other things, have been focused on the longstanding dual epidemics of TB and HIV. As with these dual epidemics, inadequate resources and poor case identification and reporting may be contributing to underestimations of the COVID-19 case burden in SSA. Modelling studies predict that the pandemic-related disruptions in TB and HIV services will result in significant increases in associated morbidity and mortality over the next five years. Furthermore, limited empirical evidence suggests that SARS-CoV-2 coinfections with TB and HIV are associated with increased mortality risk in SSA. However, predictive models require a better evidence-base to accurately define the impact of COVID-19, not only on communicable diseases such as TB and HIV, but on non-communicable disease comorbidities. Further research is needed to assess morbidity and mortality data among both adults and children across the African continent, paying attention to geographic disparities, as well as the clinical and socio-economic determinants of COVID-19 in the setting of TB and/or HIV.

Single Dose Abacavir Pharmacokinetics and Safety in Neonates Exposed to Human Immunodeficiency Virus (HIV).

Abacavir is a potential option for prophylaxis and early treatment of human immunodeficiency virus (HIV), but no data are available in neonates. Ten neonates administered a single abacavir dose of 8 mg/kg before 15 days of life had substantially higher exposures than those reported in infants and children, with no reported adverse events.

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

BACKGROUND: South Africa has one of the highest tuberculosis incidence rates. Biologic disease-modifying anti-rheumatic drugs are associated with an increased risk of tuberculosis. The objective of this study was to describe the tuberculosis disease incidence rate among public sector patients receiving biologic therapies in the Western Cape Province. METHODS: A retrospective, descriptive analysis was undertaken using routine health data collated by the Provincial Health Data Centre from January 2007 (first use of biologic therapy in the Western Cape) to September 2018. RESULTS: We identified 609 patients treated with tumour necrosis factor-alpha (TNF-α) or non-TNF-α biologic therapies. Thirty-seven (37) patients developed tuberculosis after biologic therapy exposure, of whom the majority (78%) had an immune mediated inflammatory disease and the remainder (22%) a haematologic malignancy. The incidence rate of tuberculosis per 100,000 person-years was 2227 overall [95% confidence interval (CI): 1591, 3037]. Patients treated with TNF-α inhibitors and non-TNF-α inhibitors had estimated incidence rates of 2819 [95% CI: 1669, 4480] and 1825 [95% CI: 1131, 2797], respectively (p = 0.10). CONCLUSION: Patients exposed to both TNF-α and non-TNF-α biologic therapies may have a higher incidence of tuberculosis disease compared to the background risk of 681 cases per 100,000 per year in the Western Cape.

Accelerating Clinical Evaluation of Repurposed Combination Therapies for COVID-19.

As the global COVID-19 pandemic continues, unabated and clinical trials demonstrate limited effective pharmaceutical interventions, there is a pressing need to accelerate treatment evaluations. Among options for accelerated development is the evaluation of drug combinations in the absence of prior monotherapy data. This approach is appealing for a number of reasons. First, combining two or more drugs with related or complementary therapeutic effects permits a multipronged approach addressing the variable pathways of the disease. Second, if an individual component of a combination offers a therapeutic effect, then in the absence of antagonism, a trial of combination therapy should still detect individual efficacy. Third, this strategy is time saving. Rather than taking a stepwise approach to evaluating monotherapies, this strategy begins with testing all relevant therapeutic options. Finally, given the severity of the current pandemic and the absence of treatment options, the likelihood of detecting a treatment effect with combination therapy maintains scientific enthusiasm for evaluating repurposed treatments. Antiviral combination selection can be facilitated by insights regarding SARS-CoV-2 pathophysiology and cell cycle dynamics, supported by infectious disease and clinical pharmacology expert advice. We describe a clinical evaluation strategy using adaptive combination platform trials to rapidly test combination therapies to treat COVID-19.