Clinical impact of plasma concentrations of first-line antituberculosis drugs.

BACKGROUND: The clinical significance of low antituberculosis (anti-TB) drug concentrations has not been fully elucidated. OBJECTIVES: To investigate the clinical consequences of first-line drug concentrations in adult patients with drug-susceptible pulmonary TBin South Africa (SA). METHOD: We conducted a pharmacokinetic study nested within the control arm of the Improving Treatment Success (IMPRESS) trial(NCT02114684) in Durban, SA. During the first 2 months of treatment, participants received weight-based dosing of first-line anti-TBdrugs (rifampicin, isoniazid, pyrazinamide and ethambutol), and had plasma drug concentrations measured at 2 and 6 hours after drugadministration during the 8th week of treatment. Intermediate (8 weeks), end-of-treatment (6 months) and follow-up TB outcomes wereassessed using World Health Organization criteria. RESULTS: We measured plasma drug concentrations on available samples in 43 participants. Peak drug concentrations were below thetherapeutic range in 39/43 (90.7%) for rifampicin, 32/43 (74.4%) for isoniazid, 27/42 (64.3%) for pyrazinamide and 5/41 (12.2%) forethambutol. At the end of the intensive phase of treatment (week 8), 20.9% (n=9/43) of participants remained culture positive. We did notfind a relationship between the concentrations of first-line drugs and treatment outcomes at week 8. All participants were cured at the endof treatment, and there were no relapses during the 12-month follow-up period. CONCLUSION: Treatment outcomes were favourable despite low drug concentrations as defined by current reference thresholds.

The utility of brain natriuretic peptide as a prognosticating marker in critical care patients.

Background: Brain natriuretic peptide (BNP) is an established biomarker of morbidity and mortality in cardiac failure. Data also suggest potential prognostic utility in non-heart failure cohorts. The utility of BNP in predicting intensive care unit (ICU) outcomes has not been well evaluated in a mixed critical care population in the South African (SA) context. Objectives: To evaluate the ability of BNP to predict ICU mortality in a heterogeneous critical care population in SA. Methods: This was a retrospective observational study of 100 patients admitted to a multidisciplinary, closed, intensivist-run ICU in a tertiary academic hospital serving KwaZulu-Natal Province (1 January 2020 - 31 July 2022). Initial BNP was evaluated as a predictor of ICU mortality using univariate and multivariable analyses. Results: There was a statistically significant difference in BNP between survivors and non-survivors in the cohort of patients without heart failure. The median initial BNP in the non-heart failure cohort was 411 (interquartile range (IQR) 116 - 848) ng/L in non-survivors, and 150 (44 - 356) ng/L in survivors (p=0.028). The optimal cut-off for BNP was determined as 366 ng/L. A BNP ≥366 ng/L was an independent predictor of ICU outcome. Conclusion: This study highlights the potential utility of BNP as a predictor of ICU mortality in a heterogeneous ICU population, with the greatest utility in patients without heart failure. Further studies are required to confirm this finding. Contribution of the study: The study is a retrospective, observational study conducted in multidisciplinary, closed, intensivist-run ICU at a tertiary academic hospital. It showed an elevated BNP is associated with increased ICU mortality, particularly in those without a baseline diagnosis of heart failure. This identifies the need for further prospective studies evaluating BNP as a prognostic marker in non-cardiac critically ill patients, and its utility as an addition in pre-existing ICU outcome prediction scores.

Altered drug exposures of first-line TB drugs in a moxifloxacin-containing treatment regimen.

BACKGROUND: Pharmacokinetic variability arising from drug-drug interactions and pharmacogenetics may influence the effectiveness of treatment regimens for TB. The Improving Treatment Success Trial compared the WHO-recommended standard treatment in TB patients with an experimental regimen substituting ethambutol with moxifloxacin (MFX) in Durban, South Africa.METHODS: Non-linear mixed-effects modelling was used to investigate the population pharmacokinetics of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA). A total of 25 single-nucleotide polymorphisms, including pregnane-X-receptor, were selected for analysis.RESULTS: TB drug concentrations were available in a subset of 101 patients: 58 in the MFX arm and 43 in the control arm. Baseline characteristics were well-balanced between study arms: median age and weight were respectively 36 years and 57.7 kg; 75.2% of the patients were living with HIV. Although weight-based drug dosing was the same in the two arms, we found that RIF exposure was increased by 19.3%, INH decreased by 19% and PZA decreased by 19.2% when administered as part of the MFX-containing regimen. Genetic variation in pregnane-X-receptor (rs2472677) was associated with a 25.3% reduction in RIF exposure.CONCLUSION: Optimised weight-based TB treatment dosing is essential when RIF, INH and PZA are co-administered with fluoroquinolones. The reduction in RIF exposure associated with pharmacogenetic variation is worrying.

A systematic review and meta-analysis of first-line tuberculosis drug concentrations and treatment outcomes.

Low serum concentrations of first-line tuberculosis (TB) drugs have been widely reported. However, the impact of low serum concentrations on treatment outcome is less well studied. A systematic search of MEDLINE/Pubmed and the Cochrane Central Register of Controlled Trials up to 31 March 2018 was conducted for articles describing drug concentrations of first-line TB drugs and treatment outcome in adult patients with drug-susceptible TB. The search identified 3073 unique publication abstracts, which were reviewed for suitability: 21 articles were acceptable for inclusion in the qualitative analysis comprising 13 prospective observational cohorts, 4 retrospective observational cohorts, 1 case-control study and 3 randomised controlled trials. Data for meta-analysis were available for 15 studies, 13 studies of rifampicin (RMP), 10 of isoniazid (INH), 8 of pyrazinamide (PZA) and 4 of ethambutol (EMB). This meta-analysis revealed that low PZA concentration appears to increase the risk of poor outcomes (8 studies, n = 2727; RR 1.73, 95%CI 1.10-2.72), low RMP concentrations may slightly increase the risk of poor outcomes (13 studies, n = 2753; RR 1.40, 95%CI 0.91-2.16), whereas low concentrations of INH (10 studies, n = 2640; RR 1.32, 95%CI 0.66-2.63) and EMB (4 studies, n = 551; RR 1.12, 95%CI 0.41-3.05) appear to make no difference to treatment outcome. There was no significant publication bias or between-study heterogeneity in any of the analyses. The potential clinical impact of low concentrations of PZA and RMP warrants further evaluation. Also, comprehensive assessments of the complex pharmacokinetic-pharmacodynamic relationships in the treatment of TB are urgently needed.

Cost of ADHD treatment using methylphenidate and atomoxetine in the South African private healthcare sector.

Introduction: The prevalence of Attention-Deficit/Hyperactivity Disorder (ADHD) has risen over the last two decades, with a corresponding increase in the cost of its medication. Drug utilization studies in South Africa focusing on ADHD are limited.Areas covered: The primary aim was to determine the cost of methylphenidate and atomoxetine (used for ADHD). The Intercontinental Marketing Service (IMS) database which contains data of the private healthcare sector was interrogated from 2013 to 2016 (48-month period) focussing on methylphenidate and atomoxetine. Drug consumption was expressed in number of DDDs, DDDs/1000 inhabitants/day and cost in Rands.Expert opinion: Methylphenidate-containing products constituted a considerably higher percentage of the market share when compared to atomoxetine (90.30% versus 9.70%). The DDD/1000 inhabitants/day for methylphenidate was 6.010 with an annual cost for R266 691 778 in 2013, which increased to 7.827 DDDs/1000 inhabitants/day with an annual cost of R436 041 506 in 2016. Consumption of both methylphenidate and atomoxetine increased from 2013 to 2016. There was a preference for long-acting extended-release methylphenidate tablets even though the unit costs were higher when compared to the short-acting formulations. Despite increases in unit costs, the spend in South Africa showed an upward trend for methylphenidate and atomoxetine.

"A tale of two cities." A snapshot survey of neurosurgical procedures performed in public and private sectors in eThekwini.

SUMMARY: Access to neurosurgical care in South Africa is influenced by prevailing inequities in healthcare. It is generally perceived that the public sector performs mainly emergencies relating to trauma, and the private sector performs mainly elective spinal surgery. In March 2015, emergencies constituted 51% of cases in the public sector compared to 8% in the private sector. Trauma, paediatric hydrocephalus and intracranial sepsis constituted nearly 75% of the operative workload in the public sector. Cranial surgery accounted for the majority (95%) of operations in the public sector, whereas the majority in the private sector was spinal (75%). There is considerable disparity in the type of neurosurgery being performed in the public and private sectors in KwaZulu-Natal and with the current financial constraints, there is a potential unmet need for elective spinal surgery in the public sector.

Review of adult attention-deficit/hyperactivity disorder in South Africa.

INTRODUCTION: Recently, there has been a greater focus on adults with Attention-Deficit/Hyperactivity Disorder (ADHD) given that the symptoms persist in two-thirds of patients into adulthood. Areas covered: A systematic review of articles reporting on adult ADHD in SA was undertaken. From the database search, 1209 articles were identified, with 29 articles included in this analysis. Expert commentary: Fourteen of the 29 studies reviewed were exploratory, 10 were reviews/commentaries, four were developmental studies and one was a phenomenological study. More than half (58.62%) of the articles were published in local South African journals, 13.79% were published in African journals (excluding South Africa), and 27.59% of the articles were published in international journals. The impact factor for nine of the journals were not stated and the remaining 11 have impact factors ranging from 0.207 to 6.78. In 2004, only one article on adult ADHD was published in SA and by 2015, the number of publications increased to six. Adult ADHD is gaining interest in South Africa, however, there have been a limited number of studies conducted thus far. It is recommended that further studies are conducted in this new and developing field.

Implementing isoniazid preventive therapy in a tuberculosis treatment-experienced cohort on ART.

SETTING: Urban clinical research site in Durban, South Africa. OBJECTIVE: To describe outcomes associated with the implementation of isoniazid preventive therapy (IPT) in a cohort of tuberculosis (TB) treatment-experienced human immunodeficiency virus (HIV) infected patients on antiretroviral therapy (ART). DESIGN: We conducted a secondary analysis of data collected between October 2009 and October 2013 from patients enrolled in a prospective cohort study conducted in Durban, South Africa. RESULTS: Of the 402 patients enrolled in the parent study, 344 (85.6%) were eligible for IPT, 212 of whom (61.6%) initiated IPT. Of those who initiated IPT, 184 (86.8%) completed the 6-month course, while 24 (11.3%) permanently discontinued IPT, 3.8% of whom due to side effects. More women than men initiated IPT (n = 130, 61.3% vs. n = 82, 38.7%, P = 0.001). Overall median adherence to IPT was 97.6% (interquartile range 94.2-99.4). There were 22 cases of incident TB in this cohort: 13 occurred before IPT and 9 after (incidence rate ratio 0.67, 95%CI 0.29-1.58, P = 0.362). CONCLUSIONS: IPT implementation among ART and TB treatment-experienced patients was well tolerated, with good completion rates and fewer TB cases diagnosed after IPT.

Incidence of pulmonary embolism after the first 3 months of spinal cord injury.

BACKGROUND: Pulmonary embolism (PE) is a significant cause of morbidity and mortality in patients with spinal cord injury (SCI). Prophylactic anticoagulation is associated with a reduction in mortality rates, but there is limited evidence regarding the incidence rate of PE following cessation of anticoagulation after the first 3 months of injury. STUDY DESIGN: Single-centre retrospective study. OBJECTIVE: To estimate the incidence rate of PE after 90 days of SCI. SETTING: The National Spinal Injuries Centre at Stoke Mandeville Hospital, Aylesbury, UK. METHODS: The study includes 640 new-onset SCI patients. All computer tomography pulmonary angiograms (CTPAs) or ventilation-perfusion lung scans between 2008 and 2013 were identified. Medical notes and scans were reviewed and clinical outcomes and radiological findings were recorded. RESULTS: A total of 91 patients with a new-onset SCI had a CTPA or a perfusion lung scan. PE was detected in a total of 8 patients. The incidence of PE was 1.25%; 95% confidence interval (0.39-2.11) over a 6-year period. The duration of injury at the time of PE was 7 months. CONCLUSION: The incidence rate of PE post 3 months of SCI remains significant, though much lower than immediately post injury.

Tuberculosis in medical doctors - a study of personal experiences and attitudes.

BACKGROUND: The concurrent TB and HIV epidemics in sub-Saharan Africa place all health care workers (HCWs) at increased risk of exposure to Mycobacterium tuberculosis. AIM: This study explores personal experiences, attitudes and perceptions of medical doctors following treatment for TB within the healthcare system. METHOD: Sixty-two medical doctors who were diagnosed and treated for TB during 2007 - 2009 agreed to participate and complete a semi-structured questionnaire. RESULTS: The response rate was 64.5% (N=40). Mean age ±SD of participants was 33.7±10.6 years. A correct diagnosis of TB was made within 7 days of clinical presentation in 20% of participants, and was delayed beyond 3 weeks in 52.5%. Non-routine special investigations and procedures were performed in 26 participants. Complications following invasive procedures were reported by 8 participants. Multi-drug resistant TB (MDR-TB) was diagnosed in 4 participants. Nineteen considered defaulting on their treatment because of drug side-effects. The majority (n=36) expressed concerns regarding lack of infection control at the workplace, delays in TB diagnosis and negative attitudes of senior medical colleagues and administrators. Ninety per cent of participants indicated that their personal illness experiences had positively changed their professional approach to patients in their current practice. CONCLUSION: The inappropriate delays in diagnosis in a large number of participants, coupled with a number of negative personal perceptions towards their treatment, are cause for concern. The results further amplify the need for improved educational and awareness programmes among all healthcare personnel (including hospital administrators), adherence to national health guidelines, effective infection control measures, pre- and post-employment screening in all HCWs, and changes in attitudes on the part of senior medical colleagues and administrators.

Resistance to antiretroviral drugs in newly diagnosed, young treatment-naïve HIV-positive pregnant women in the province of KwaZulu-Natal, South Africa.

In 2004, KwaZulu-Natal initiated one of the world's largest HIV/AIDS treatment programs. Studies in South Africa have shown that patients on antiretroviral therapy (ART) develop rapidly and transmit drug resistant mutations. Since resistance testing is not widely available in Kwazulu-Natal, the Department of Health conducted the first HIV drug resistance (HIVDR) threshold survey in 2005, which did not identify any mutations associated with HIVDR. The objective of this study was to conduct a follow-up threshold survey to update the information on HIVDR. This study was conducted in 2009 in five antenatal care sites in Kwazulu-Natal using the HIVDR threshold survey method developed by WHO. Two hundred and thirteen newly-diagnosed HIV positive, drug-naïve primigravidae, less than 22 years of age were included in the survey. Of the 82 HIV positive specimens, 17 had insufficient volume for genotyping and, of the remaining 65, 47 were genotyped sequentially. Drug resistance was identified by sequencing the HIV-1 pol gene, using the ViroSeq® HIV-1 genotyping system v2.0. Of the 47 samples that were genotyped, only one presented with a K103N mutation, which equates to a prevalence of transmitted HIVDR of <5%. The low prevalence of transmitted HIVDR is in keeping with statistical models of the early stages of ART rollout. As ART coverage is increasing continuously, there is a need to ensure that vigilance of HIVDR continues so that the emergence and spread of HIVDR is minimized.

Vasectomy under local anaesthesia performed free of charge as a family planning service: complications and results.

OBJECTIVE: To evaluate the safety and efficacy of vasectomy performed under local anaesthesia by junior doctors at a secondary level hospital as part of a free family planning service. METHOD: Men requesting vasectomy were counselled and given written instructions to use alternative contraception until two semen analyses 3 and 4 months after vasectomy had confirmed azoospermia. Bilateral vasectomy was performed as an outpatient procedure under local anaesthesia by junior urology registrars. Statistical analysis was performed using the Mann-Whitney, Kruskal-Wallis, Fisher's exact or Spearman's rank correlation tests as appropriate. RESULTS: Between January 2004 and December 2005, 479 men underwent vasectomy at Karl Bremer Hospital, Western Cape, South Africa; their average age was 36.1 (range 21 - 66) years, they had a median of 2 (range 0 - 10) children, and only 19% had 4 or more children. The average operation time was 15.5 (range 5 - 53) minutes. Complications occurred in 12.9%; these were pain (7.3%), swelling (5.4%), haematoma (1.3%), sepsis (1%), difficulty locating the vas (1%), vasovagal episode (0.6%), bleeding (0.6%), wound rupture (0.4%) and dysuria (0.2%) (some men had more than one complication). Of the men 63.3% returned for one semen analysis and 17.5% for a second. The vasectomy failure rate ranged from 0.4% (sperm persisting > 365 days after vasectomy) to 2.3% (sperm seen > 180 days after vasectomy and/or in the second semen specimen). No pregnancies were reported. The complication (5.6%) and failure rates (0%) were lowest for the registrar who had performed the smallest number of vasectomies and whose average operation time was longest. Comparing the first one-third of procedures performed by each of the doctors with the last one-third, there was a significant decrease in average operating times but not in complication rates. CONCLUSIONS: Vasectomy can be performed safely and effectively by junior doctors as an outpatient procedure under local anaesthesia, and should be actively promoted in South Africa as a safe and effective form of male contraception.

Renal vein thrombosis in transitional cell carcinoma.

A rare case of renal transitional cell carcinoma (TCC) associated with bland thrombus of the renal vein extending into the inferior vena cava is described. Tumour thrombus in renal cell carcinoma is frequently encountered, but only very rarely occurs with TCC. Bland renal vein thrombosis occurring with renal TCC has not been described before. Contrast enhanced computed tomography assisted in distinguishing between bland and tumour thrombosis and aided in surgical management.

Cholera: a continuous epidemic in Africa.

Cholera continues to plague many parts of the world, but has largely been concentrated in Africa, which contributes more than 80% of the total cases worldwide. Natural disasters, like the 2000 floods in Mozambique and the volcanic eruption in the Democratic Republic of the Congo in 2002, generally lead to new outbreaks of the disease. The refugee problem in many countries throughout the world also causes potential threats for disease outbreaks. Case fatality rates are high, and we are not anywhere near curbing new cholera epidemics, especially in Africa. It is thus imperative to renew discussions about the nature of this deadly disease, its treatment, measures for prevention and control, modes of transmission, its physical, social and economic impact, and potential solutions.

Accidental Mycobacterium bovis infection in a veterinarian.

CASE: A veterinarian developed tenosynovitis and secondary carpal tunnel syndrome following accidental inoculation of Mycobacterium bovis during the necropsy of a tuberculous possum from Westland, New Zealand. CLINICAL RELEVANCE: M. bovis infection is a zoonotic disease, and occupational exposure to tuberculous animals places people at risk of contracting the disease. CONCLUSIONS: Adhering to safe work practices reviewed in this article is important to minimise the risk of infection to people handling tuberculous animals.

Carboxylesterases, a key factor in evaluating potential genotoxicity of Trinem antibiotics.

Sanfetrinem cilexetil, a hexetil ester of a Trinem antibiotic, does not induce micronuclei in rat bone marrow cells or induce DNA repair synthesis in rat hepatocytes following oral dosing. However, in vitro chromosome damage and mutations are induced in mammalian cells lacking carboxylesterase activity (human lymphocytes and mouse lymphoma L5178Y cells). In cells possessing carboxylesterase activity (CHL cells), chromosome damage induced by Sanfetrinem cilexetil is not observed. Similarly, if induced rat liver preparations or non-induced preparations from rat or human intestinal cells are present during exposure, genotoxic activity is lost, even in those cells lacking carboxylesterase enzymes. Thus the lack of demonstrable genotoxicity in vivo, in the assays used, is likely to be due to hydrolysis of the parent molecule by non-specific carboxylesterases present within the intestinal epithelium. In turn this data indicates that a genotoxic hazard to humans under therapeutic conditions is unlikely.

Black South African students' use of counseling service.

This paper reports the demographic and summative annual data for presenting concerns of students seeking counseling at a Black South African university. Rankings of the major presenting concerns identified by the clients are presented.

Sex education sources and attitudes about premarital sex of Seventh Day Adventist youth.

37 Seventh Day Adventist youth were surveyed about their sex education and attitudes towards premarital sex. Analysis indicated differences between their attitudes and actual sexual behaviour. While 70% endorsed the church's prohibition on premarital sex, 54% had engaged in premarital sex.

Comparison of Salmonella typhimurium TA102 with Escherichia coli WP2 tester strains.

In 1982, Levin et al. published a paper describing a new Salmonella typhimurium strain, TA102, for detecting mutagenic agents that react preferentially with AT base pairs. This strain has an AT base pair at the critical mutation site within the hisG gene, which is located on a multicopy plasmid, pAQ1; the chromosomal copy of the hisG gene has been deleted. It also has an intact excision repair system, thus facilitating the detection of cross-linking agents, and carries the mutator plasmid, pKM101. Although TA102 has been shown to be reverted by certain mutagenic agents that are not detected in the usual battery of strains (TA1535, TA1537, TA1538, TA98 and TA100), there has been a general reluctance within the field to include TA102 as one of the standard screening strains. This may in part result from the difficulties which have been experienced in many laboratories in maintaining the strain, and in obtaining reproducible spontaneous and induced revertant counts. At Glaxo we routinely include certain Escherichia coli strains in our microbial test battery, and were aware that some of the genetic features offered by TA102 were already being covered by these strains. For example, E.coli WP2 (pKM101) has an AT base pair at the critical mutation site within the trpE gene, is excision proficient (and thus will detect cross-linking agents) and carries the pKM101 plasmid to enhance error-prone repair. From the published literature it was apparent that a number of the 'TA102 specific' mutagens could be detected in E.coli e.g. neocarzinostatin, UV and 8-MOP plus UV.(ABSTRACT TRUNCATED AT 250 WORDS)