Surgeon variation: a south african spinal pathology treatment survey.

PURPOSE: To investigate variation in treatment decisions among spine surgeons in South Africa and the association between surgeon characteristics and the treatment they select. METHODS: We surveyed 79 South African spine surgeons. We presented four vignettes (cervical spine distractive flexion injury, lumbar disc herniation, degenerative spondylolisthesis with stenosis, and insufficiency fracture) for them to assess and select treatments. We calculated the index of qualitative variation (IQV) to determine the degree of variability within each vignette. We used Fisher's exact, and Kruskal-Wallis tests to assess the relationships between surgeons' characteristics and their responses per vignette. We compared their responses to the recommendations of a panel of spine specialists. RESULTS: IQVs showed moderate to high variability for cervical spine distractive flexion injury and insufficiency fracture and slightly lower levels of variability for lumbar disc herniation and degenerative spondylolisthesis with stenosis. This confirms the heterogeneity in South African spine surgeons' management of spinal pathologies. The surgeon characteristics associated with their treatment selection that were important were caseload, experience and training, and external funding. Also, 19% of the surgeons selected a treatment option that the Panel did not support. CONCLUSION: The findings make a case for evaluating patient outcomes and costs to identify value-based care. Such research would help countries that are seeking to contract with providers on value. Greater uniformity in treatment and easily accessible outcomes reporting would provide guidance for patients. Further investment in training and participation in fellowship programs may be necessary, along with greater dissemination of information from the literature.

Regeneration of Pancreatic Beta Cells by Modulation of Molecular Targets Using Plant-Derived Compounds: Pharmacological Mechanisms and Clinical Potential.

Type 2 diabetes (T2D) is characterized by pancreatic beta-cell dysfunction, increased cell death and loss of beta-cell mass despite chronic treatment. Consequently, there has been growing interest in developing beta cell-centered therapies. Beta-cell regeneration is mediated by augmented beta-cell proliferation, transdifferentiation of other islet cell types to functional beta-like cells or the reprograming of beta-cell progenitors into fully differentiated beta cells. This mediation is orchestrated by beta-cell differentiation transcription factors and the regulation of the cell cycle machinery. This review investigates the beta-cell regenerative potential of antidiabetic plant extracts and phytochemicals. Various preclinical studies, including in vitro, in vivo and ex vivo studies, are highlighted. Further, the potential regenerative mechanisms and the intra and extracellular mediators that are of significance are discussed. Also, the potential of phytochemicals to translate into regenerative therapies for T2D patients is highlighted, and some suggestions regarding future perspectives are made.

Lupus myocarditis: review of current diagnostic modalities and their application in clinical practice.

Lupus myocarditis (LM) is a potentially fatal manifestation of SLE, occurring in 5-10% of patients. Clinical manifestations may vary from an unexplained tachycardia to fulminant congestive cardiac failure (CCF). With no single clinical or imaging modality being diagnostic, a rational and practical approach to the patient presenting with possible LM is essential. Markers of myocyte injury (including troponin I and creatine kinase) may be unelevated and do not exclude a diagnosis of LM. Findings on ECG are non-specific but remain essential to exclude other causes of CCF such as an acute coronary syndrome or conduction disorders. Echocardiographic modalities including wall motion abnormalities and speckle tracking echocardiography may demonstrate regional and/or global left ventricular dysfunction and is more sensitive than conventional echocardiography, especially early in the course of LM. Cardiac magnetic resonance imaging (CMRI) is regarded as the non-invasive diagnostic modality of choice in myocarditis. While more sensitive and specific than echocardiography, CMRI has certain limitations in the context of SLE, including technical challenges in acutely unwell and uncooperative patients, contraindications to gadolinium use in the context of renal impairment (including lupus nephritis) and limited literature regarding the application of recommended diagnostic CMRI criteria in SLE. Both echocardiography as well as CMRI may detect subclinical myocardial dysfunction and/or injury of which the clinical significance remains uncertain. Considering these challenges, a combined decision-making approach by rheumatologists and cardiologists interpreting diagnostic test results within the clinical context of the patient is essential to ensure an accurate, early diagnosis of LM.

Therapeutic Benefit in Rheumatoid Cachexia Illustrated Using a Novel Primary Human Triple Cell Coculture Model.

Background: The loss of muscle mass in rheumatoid arthritis (RA), termed rheumatoid cachexia, is predicted to result from the complex interactions between different cell types involved in the maintenance of skeletal muscle mass, namely, myoblasts, fibroblasts, and macrophages. The complexity within the muscle is further highlighted by the incidence of nonresponsiveness to current RA treatment strategies. Method: This study aimed at determining differences in the cellular responses in a novel human primary cell triple coculture model exposed to serum collected from nonarthritic controls (NC), RA treatment naïve (RATN), and RA treatment-nonresponding (RATNR) patients. Bone morphogenetic protein-7 (BMP-7) was investigated as a treatment option. Results: Plasma analysis indicated that samples were indeed representative of healthy and RA patients-notably, the RATNR patients additionally exhibited dysregulated IL-6/IL-10 correlations. Coculture exposure to serum from RATNR patients demonstrated increased cellular growth (p < 0.001), while both hepatocyte growth factor (p < 0.01) and follistatin (p < 0.001) were reduced when compared to NC. Furthermore, decreased concentration of markers of extracellular matrix formation, transforming growth factor-ß (TGF-ß; p < 0.05) and fibronectin (p < 0.001), but increased collagen IV (p < 0.01) was observed following RATNR serum exposure. Under healthy conditions, BMP-7 exhibited potentially beneficial results in reducing fibrosis-generating TGF-ß (p < 0.05) and fibronectin (p < 0.05). BMP-7 further exhibited protective potential in the RA groups through reversing the aberrant tendencies observed especially in the RATNR serum-exposed group. Conclusion: Exposure of the triple coculture to RATN and RATNR serum resulted in dysregulated myoblast proliferation and growth, and ECM impairment, which was reversed by BMP-7 treatment.

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.

A retrospective review of calls to the Poisons Information Helpline of the Western Cape during the first 6 months of the COVID-19 pandemic in South Africa.

Background: Since the start of the coronavirus disease 2019 (COVID-19) pandemic, poison centres worldwide have reported an increase in exposures to chemicals used for infection prevention. Increased availability and use could lead to an increase in exposures. Potential effects on a South African Poison Information Helpline were unknown, therefore a study was performed to describe changes in call volume and profile of poison exposures. Methods: A retrospective analysis was conducted on an observational database of telephone enquiries. All human-related poisoning exposure call data collected from 01 March to 31 August during 2018, 2019 and 2020 were extracted and analysed. Summary statistics were used to describe all variables. Results: The total number of calls were 5137, 5508, and 5181 in 2018, 2019, 2020, respectively. The monthly call number during 2020 was mostly less than in 2019. More calls were received from the public calls (39.4% vs 33.1%) and for accidental exposures (65.6% vs 62.3%) increased during 2020 compared to 2019. Exposures to pharmaceuticals decreased by 14.8% from 2019 to 2020, while exposures to eucalyptus oil more than doubled from 21 in 2019 to 43 during 2020. Exposures to antiseptics and disinfectants increased by 60.4%, mainly due to hand sanitisers exposure which showed a 26-fold increase from 2019 (n = 6) to 2020 (n = 156). Conclusion: A change in the profile of poison exposures was observed during the COVID-19 pandemic. Lockdown regulations and greater availability of antiseptics and disinfectants probably led to the increase in exposures. Although symptoms were mostly mild, the public should be educated on safe storage and proper use of all chemicals.

A retrospective review of calls to the Poisons Information Helpline of the Western Cape during the first 6 months of the COVID-19 pandemic in South Africa

Background: Since the start of the coronavirus disease 2019 (COVID-19) pandemic, poison centres worldwide have reported an increase in exposures to chemicals used for infection prevention. Increased availability and use could lead to an increase in exposures. Potential effects on a South African Poison Information Helpline were unknown, therefore a study was performed to describe changes in call volume and profile of poison exposures. Methods: A retrospective analysis was conducted on an observational database of telephone enquiries. All human-related poisoning exposure call data collected from 01 March to 31 August during 2018, 2019 and 2020 were extracted and analyzed. Summary statistics were used to describe all variables. Results: The total number of calls were 5137, 5508, and 5181 in 2018, 2019, 2020, respectively. The monthly call number during 2020 was mostly less than in 2019. More calls were received from the public calls (39.4% vs 33.1%) and for accidental exposures (65.6% vs 62.3%) increased during 2020 compared to 2019. Exposures to pharmaceuticals decreased by 14.8% from 2019 to 2020, while exposures to eucalyptus oil more than doubled from 21 in 2019 to 43 during 2020. Exposures to antiseptics and disinfectants increased by 60.4%, mainly due to hand sanitizers exposure which showed a 26-fold increase from 2019 (n = 6) to 2020 (n = 156). Conclusion: A change in the profile of poison exposures was observed during the COVID-19 pandemic. Lockdown regulations and greater availability of antiseptics and disinfectants probably led to the increase in exposures. Although symptoms were mostly mild, the public should be educated on safe storage and proper use of all chemicals.

The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis.

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.

Higher SARS-CoV-2 seroprevalence in workers with lower socioeconomic status in Cape Town, South Africa.

BACKGROUND: Inequality is rife throughout South Africa. The first wave of COVID-19 may have affected people in lower socioeconomic groups worse than the affluent. The SARS-CoV-2 seroprevalence and the specificity of anti-SARS-CoV-2 antibody tests in South Africa is not known. METHODS: We tested 405 volunteers representing all socioeconomic strata from the workforce of a popular shopping and tourist complex in central Cape Town with the Abbott SARS-CoV-2 IgG assay. We assessed the association between antibody positivity and COVID-19 symptom status, medical history, and sociodemographic variables. We tested 137 serum samples from healthy controls collected in Cape Town prior to the COVID-19 pandemic, to confirm the specificity of the assay in the local population. RESULTS: Of the 405 volunteers tested one month after the first peak of the epidemic in Cape Town, 96(23.7%) were SARS-CoV-2 IgG positive. Of those who tested positive, 46(47.9%) reported no symptoms of COVID-19 in the previous 6 months. Seropositivity was significantly associated with living in informal housing, residing in a subdistrict with low income-per household, and having a low-earning occupation. The specificity of the assay was 98.54%(95%CI 94.82%-99.82%) in the pre-COVID controls. CONCLUSIONS: There is a high background seroprevalence in Cape Town, particularly in people of lower socioeconomic status. Almost half of cases are asymptomatic, and therefore undiagnosed by local testing strategies. These results cannot be explained by low assay specificity.

Outcome of clinical and subclinical myocardial injury in systemic lupus erythematosus - A prospective cohort study.

OBJECTIVES: To determine the outcome of subclinical lupus myocarditis (LM) over twelve months with regards to: mortality; incidence of clinical LM and change in imaging parameters (echocardiography and cardiac magnetic resonance [CMR]). To evaluate the impact of immunosuppression on CMR evidence of myocardial tissue injury. METHODS: SLE patients with and without CMR evidence of myocardial injury (as per 2009 Lake Louise criteria [LLC]) were included. Analysis at baseline and follow-up included: clinical evaluation, laboratory and imaging analyses (echocardiography and CMR). Clinical LM was defined as clinical features of LM supported by echocardiographic and/or biochemical evidence of myocardial dysfunction. Subclinical LM was defined as CMR myocardial injury without clinical LM. RESULTS: Forty-nine SLE patients were included with follow-up analyses (after 12 months) available in 36 patients. Twenty-five patients (51%) received intensified immunosuppressive therapy during follow-up for indications related to SLE. Disease activity (SLEDAI-2K) improved (p < 0.001) from 13 (median;IQR:9-20) to 7 (3-11). One patient without initial CMR evidence of myocardial injury developed clinical LM. Mortality (n = 10) and SLE clinical features were similar between patients with and without initial CMR myocardial injury. Echocardiographic left ventricular ejection fraction (LVEF) (p = 0.014), right ventricular function (p = 0.001) and wall motion abnormalities (p = 0.056) improved significantly but not strain analyses nor the left LV internal diameter index. CMR mass index (p = 0.011) and LVEF (p < 0.001) improved with follow-up but not parameters identifying myocardial tissue injury (LLC). A trend towards a reduction in the presence of CMR criteria was counterbalanced by persistence (n = 7) /development of new criteria (n = 11) in patients. Change in CMR mass index correlated with change in T2-weighted signal (myocardial oedema) (r = 386;p = 0.024). Intensified immunosuppressive therapy had no significant effect on CMR parameters. CONCLUSION: CMR evidence of subclinical LM persisted despite improved SLEDAI-2K, serological markers, cardiac function and CMR mass index. Subclinical LM did not progress to clinical LM and had no significant prognostic implications over 12 months. Immunosuppressive therapy did not have any significant effect on the presence of CMR evidence of myocardial tissue injury. Improvement in CMR mass index correlated with reduction in myocardial oedema and may be used to monitor SLE myocardial injury.

Serum cytokine levels associated with myocardial injury in systemic lupus erythematosus.

OBJECTIVES: To identify cytokines, markers of endothelial activation [soluble vascular cell adhesion molecule-1 (sVCAM-1)] and myocyte strain [soluble ST2 (sST2)] associated with myocardial injury (MInj) in SLE, classified by cardiac magnetic resonance (CMR) criteria. METHODS: CMR was performed on patients with SLE, identifying stages of MInj (inflammation and necrosis or fibrosis). Data captured included: clinical assessment, laboratory and serological analyses, cytokine (IL-1ß, IL-1Ra, IL-2, IL-6, IL-10, IL-17, IL-18, TNF-alpha), sVCAM-1 and sST2 levels. Cytokines were compared with regard to SLE features and evidence of CMR MInj. Predictors of CMR MInj were determined through regression analyses. RESULTS: Forty-one patients with high disease activity (SLEDAI-2K: 13; IQR: 3-17) were included. SLE features included: LN (n = 12), neurolupus (n = 6) and clinical lupus myocarditis (LM) (n = 6). Nineteen patients had CMR evidence of MInj. Patients with a SLEDAI-2K ≥ 12 had higher sVCAM-1 (P = 0.010) and sST2 (P = 0.032) levels. Neurolupus was associated with higher IL-1Ra (P = 0.038) and LN with lower IL-1Ra (P = 0.025) and sVCAM-1 (P = 0.036) levels. Higher IL-1Ra (P = 0.012), IL-17 (P = 0.045), IL-18 (P = 0.003), and sVCAM-1 (P = 0.062) levels were observed in patients with CMR MInj compared with those without. On multivariable logistic regression, IL-1Ra predicted CMR inflammation and fibrosis/necrosis (P < 0.005) while anti-Ro/SSA [odds ratio (OR): 1.197; P = 0.035] and the SLE damage index (OR: 4.064; P = 0.011) predicted fibrosis/necrosis. CONCLUSION: This is a novel description of associations between cytokines and SLE MInj. IL-18 and IL-1Ra were significantly higher in patients with MInj. IL-1Ra independently predicted different stages of CMR MInj. Exploration of the role of these cytokines in the pathogenesis of SLE MInj may promote targeted therapies for LM.

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.

Myocardial injury in systemic lupus erythematosus according to cardiac magnetic resonance tissue characterization: clinical and echocardiographic features.

OBJECTIVES: To determine the prevalence of myocardial injury (MInj) in systemic lupus erythematosus (SLE) according to cardiac magnetic resonance (CMR) criteria. To compare clinical and echocardiographic features of patients with and without MInj and identify predictors of myocardial tissue characteristics according to CMR. METHODS: SLE inpatients underwent CMR screening for MInj based on the Lake Louise Criteria (LLC). Tissue characteristics included inflammation (increased T2-weighted signal or early gadolinium enhancement ratio (EGEr)) and necrosis or fibrosis (late gadolinium enhancement (LGE)). Echocardiographic parameters included left (left ventricular ejection fraction (LVEF)) and right ventricular function (tricuspid annular plane systolic excursion (TAPSE)), global longitudinal strain (GLS), wall motion score (WMSi) and left ventricular internal diameter index (LVIDi). Variables were compared with regards to the presence/absence of CMR criteria. Logistic regression identified variables predictive of CMR tissue characteristics. RESULTS: A hundred and six SLE patients were screened of whom 49 patients were included. Fifty-seven patients were excluded due to intolerance of or contraindication to CMR (27/57 due to renal impairment). Twenty-three patients had CMR evidence of MInj, of which 60.9% was subclinical. Inflammation occurred in 16/23 and necrosis/fibrosis in 12/23 patients. Patients with any evidence of MInj were more frequently anti-dsDNA positive (p = 0.026) and patients fulfilling LLC for myocarditis had higher SLE disease activity (p = 0.022). The LVIDi (p = 0.005), LVEF (p = 0.005) and TAPSE (p = 0.011) were more abnormal in patients with an increased EGEr, whereas WMSi (p = 0.002) and GLS (0.020) were more impaired in patients with LGE. On multivariable logistic regression analyses, TAPSE predicted inflammation (OR: 0.045, p = 0.006, CI: 0.005-0.415) and GLS predicted necrosis/fibrosis (OR: 1.329, p = 0.031, CI: 1.026-1.722). A model including lymphocyte count, TAPSE and LVIDi predicted an increased EGEr on CMR (receiver operating characteristic-curve analyses: area under the curve: 0.901, p < 0.001, sensitivity: 88.9%, specificity: 76.3%). CONCLUSIONS: CMR evidence of MInj frequently occurs in SLE and is often subclinical. The utility of CMR in SLE is limited by a high exclusion rate, mainly due to renal involvement. Models including echocardiographic parameters (TAPSE, LVIDi and GLS) are predictive of CMR myocardial injury. Echocardiography can be used as a cost-effective screening tool with a high negative predictive value, in particular when CMR is contraindicated or unavailable.

Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens.

PURPOSE: Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens. METHODS: To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER. RESULTS: The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for ≥ 98% of the dosing interval in all the evaluated PASER regimens. CONCLUSION: The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.

The pharmacokinetics of para-aminosalicylic acid and its relationship to efficacy and intolerance.

Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.

Pharmacokinetics of Para-Aminosalicylic Acid and Its 2 Major Metabolites: A Potential Relationship to the Development of Gastrointestinal Intolerance.

Para-aminosalicylic acid (PAS), often the last drug remaining for treatment of drug-resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (Cmax ) and intolerance scores. A large interindividual variability was observed for the PAS Cmax (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide Cmax range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS Cmax and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.

Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis.

The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2 µg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax ≥ 22 µg/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC6) ≥ 70 µg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.

South African Marine Envenomations and Poisonings as Managed Telephonically by the Tygerberg Poisons Information Centre: A 20-Year Retrospective Review.

INTRODUCTION: South Africa has an abundance of marine life, and the potential for hazardous exposure to marine life is high. To our knowledge, this is the first epidemiological review regarding marine toxicity that has ever been conducted in sub-Saharan Africa. The aim of this review was to investigate marine toxicology data as managed telephonically by the Tygerberg Poisons Information Centre. METHODS: Marine toxicology cases were retrospectively analyzed for a 20-y period (January 1, 1995 to December 31, 2014). Data were extracted from archived consultation forms. Descriptive statistics are presented, and post hoc analyses compared age, sex, province, and caller's background with severity and type of toxicology. RESULTS: A total of 311 calls involved 392 cases. Most calls involved adults (n=317, 81%) and males (n=214, 55%) and presented with no or minor symptoms (n=242, 62%). Poisoning from ingestion (n=239; 61%) was more commonly encountered than was marine envenomation (n=153; 39%), with paralytic shellfish poisoning (n=118; 30%), scombroid poisoning (n=93; 24%), and envenomation from stingrays (n=36; 9%) and bluebottles (n=33; 8%) occurring often. Healthcare professionals were more likely to consult for severe cases (odds ratio 3.3; 95% CI 1.9-5.9) and poisoning-related cases (odds ratio 1.8; 95% CI 1.1-2.9). CONCLUSION: The proportion of marine-related toxicology cases was low. Telephonic consultations by healthcare professionals relating to poisoning were generally of a serious nature. The data can be used to drive public health awareness campaigns.

The epidemiology and severity of scorpion envenoming in South Africa as managed by the Tygerberg Poisons Information Centre over a 10 year period.

INTRODUCTION: South Africa has a wide distribution of scorpion species, yet limited data are available regarding the incidence and severity of scorpion envenomation. The aim of this study was to analyse South African epidemiological data of scorpion stings and envenomation as reported to the Tygerberg Poisons Information Centre (TPIC). METHODS: A retrospective analysis was conducted of scorpion-related telephonic consultations to the TPIC over a ten year period (1 January 2005 to 31 December 2014). Data were entered onto a Microsoft Excel® spreadsheet and descriptive statistics are presented for all variables. Associations with severity of envenomation are presented as odds ratios (OR) with 95% confidence intervals (95%CI). RESULTS: During the study period 52,163 consultations were processed by the TPIC of which 740 (1.4%) cases involved scorpion stings. Of these, 146 (19.7%) cases were deemed serious envenomations. Antivenom was recommended to be administered in 131 (90%) of these cases. Healthcare professionals made most calls (63%), but were less likely to phone for non-serious cases (OR 0.16; 95%CI 0.09 to 0.29). The Western Cape Province had the highest incidence of calls (6.9 scorpion-related calls/100 000 people). Adults (>20 years) were victims in 71.4% of cases, and were more likely to experience less serious stings (OR 0.57; 95%CI 0.37 to 0.86). The TPIC was consulted within six hours of the sting occurring in 356 (48.1%) cases with a significant association to less severity (OR 3.51; 95%CI 1.9 to 6.3). Only 2% (15) of the scorpions were available for identification. CONCLUSION: The incidence of severe scorpionism to the TPIC was low. Care should be taken when children are involved and when calls are received more than six hours after the sting. TPIC consultants as well as healthcare professionals working in semi-arid regions should be aware of these high risk populations.