Search

MPharm (Advanced Clinical Pharmacy), North-West University, Potchefstroom Campus Background: The burden of resistant bacteria is increasing and to ensure optimal treatment with the antibiotics currently available, therapeutic drug monitoring should be performed when prescribing aminoglycosides. Aminoglycosides are very effective in treating resistant gram-negative bacteria, but their use is limited by toxicity. Therapeutic drug monitoring (TDM) is essential to ensure that aminoglycoside peak concentrations are high enough for effective antimicrobial treatment and trough levels are low enough to minimise toxicity. Toxicity of aminoglycosides include reversible renal toxicity and irreversible ototoxicity. Inappropriate utilisation of TDM may lead to suboptimal therapy, toxicity and waste of resources that are already scarce in South Africa. The study aim was to investigate the standard of aminoglycoside TDM in a South African private hospital. The study determined whether dosage changes were made when the drug levels were outside the normal ranges, whether TDM was being done according to guidelines, and if samples were drawn at the correct times. Method: Retrospective data from November 2014 to October 2016 was used in this observational, descriptive, cross-sectional study, performed in a 221-bed private hospital in the Western Cape. All adult patients, older than 18 years, who were treated with intravenous amikacin or gentamicin for more than 48 hours, were included. A computerised database and patient files were used to obtain the information required for this study. Descriptive statistical analyses were used to describe and summarise data. Results: One hundred and three (103) patients were included: 65 patients on gentamicin and 38 on amikacin. Blood levels were performed on only 19 gentamicin (29.23%) and 22 amikacin (57.89%) patients. Trough levels were taken more than 2 hours before the next dose in 12 gentamicin (63.16%) and 12 amikacin (54.54%) patients. The majority of patients (96.92% on gentamicin and 84.21% on amikacin) received once daily doses. Therapeutic drug monitoring was performed in all patients with an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73m2 and in 23.31% of gentamicin patients and 56.76% of amikacin patients with an eGFR higher than 60 mL/min/1.73m2. All samples taken were trough levels and no peak levels were done. If a blood level was too high, the next dose was omitted. Conclusions: Incorrect sampling times and unnecessary levels taken in patients with normal renal function indicate a need for aminoglycoside treatment guidelines in the private hospital. Masters

Background: Greater access and prolonged exposure to ART may inevitably lead to more treatment failure and increase the need for third-line ART (TLART) in a resource-limited setting. Objective: To describe characteristics and resistance patterns of adult patients initiated on TLART in three districts of the North West province. Method: All-inclusive retrospective descriptive investigation. Demographics and clinical variables were recorded from adult patient health records (2002-2017) and analysed. Results: 21 Patients (17 females, 4 males) with median (IQR) age of 34 years (30.2-37.8) at HIV diagnosis and 45 years (39.5-47) at TLART initiation were included. Median duration (days) from HIV diagnosis to first-line ART initiation was 101 (37-367), treatment duration on first-line, second-line and between second-line failure and TLART initiation were: 1 269 (765-2 343); 1 512 (706-2096) and 71 (58-126) days respectively. High-level resistance most prevalent were: nelfinavir/r (85.7%), indinavir/r (80.9%), lopinavir/r (76.2%), emtricitabine and lamivudine (95.2%), nevirapine (76.2%) and efavirenz (71.4%). Resistance to 3 major PI mutations in 95% of patients and cross resistance were documented extensively. Conclusion: This study support the need for earlier resistance testing. It firstly reported on time duration post diagnosis on various ART regimens and secondly resistance patterns of adults before TLART was initiated in these districts. Keywords: HIV; Human immunodeficiency virus; third-line antiretroviral therapy; drug resistance patterns; salvage therapy.

Background : Therapeutic drug monitoring (TDM) is essential to ensure that aminoglycoside peak concentrations are high enough for effective antimicrobial treatment and trough levels are low enough to minimise toxicity. Inappropriate utilisation of TDM may lead to suboptimal therapy, toxicity and waste of resources. This study aimed to investigate the standard of aminoglycoside TDM performed in adult hospitalised patients. Design : An observational, descriptive, cross-sectional study. Setting: A 221-bed private hospital. Participants : All patients, older than 18 years, on intravenous aminoglycosides for more than 48 hours were included. Interventions : None, was observational. A computerised database and patient files were used to obtain the information required for this study. Descriptive statistical analysis was used. Main outcomes measures : Aminoglycoside blood levels and estimated glomerular filtration rate (eGFR) in the patients. Results : One hundred and three (103) patients were included: 65 on gentamicin and 38 on amikacin. Blood levels were performed in only 19 gentamicin (29.23%) and 22 amikacin (57.89%) patients. Trough levels were taken more than 2 hours before the next dose in 12 gentamicin (63.16%) and 12 amikacin (54.54%) patients. The majority of patients (96.92% on gentamicin and 84.21% on amikacin) received once daily doses. TDM was performed in all patients with an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73m2 and in 23.31% of gentamicin patients and 56.76% of amikacin patients with an eGFR higher than 60 mg/min/1.73m2. Conclusions : Incorrect sampling times and unnecessary levels taken in patients with normal renal function indicate a need for aminoglycoside treatment guidelines in the private hospital. Funding : None Keywords : Aminoglycosides, Dosing considerations, South Africa, Therapeutic DrugMonitoring, Sampling times

Background: South Africa has the highest number of patients on antiretroviral therapy (ART) globally. Various obstacles were identified that influence effective reporting of adverse drug reactions (ADRs) in resource-limited countries. This investigation aimed to identify, classify and analyse the prevalence of ART-related ADRs. Methods: This observational, quantitative and retrospective descriptive investigation utilised ADR forms completed by healthcare professionals in various healthcare facilities in the Tlokwe district, South Africa (January 2010 to December 2014). Descriptive and inferential analyses were carried out. Results: A total of 770 ART-related ADRs were included in the final analysis. The mean age was 40.1 (± 10.1%) years, with significantly higher ADRs reported in females (70.8%). In this study, 99% of the ADRs were reported by doctors. Abnormal fat distribution (58%), peripheral neuropathy (21.6%) and renal dysfunction (6.6%) were most frequently reported. Females presented with abnormal fat distribution and peripheral neuropathy at a significantly younger age (38.1 ± 4.6 vs. 43.4 ± 5.7 years, p < 0.0001 and 39.7 ± 1.1 vs. 45.1 ± 9.2 years, p < 0.001) respectively compared with males. Gender difference was practically significant (Cramer’s V = 0.3) for all three of the major reported ADRs. Conclusions: Gender was highly dependent among the major reported ADR categories, and women presented with abnormal fat distribution and peripheral neuropathy at a significantly earlier age than males. This retrospective analysis can serve as a platform for future ADR studies within this district. Sustainable and continuous efforts should be made to train and create more awareness among healthcare workers in this district. (Full text of the research articles are available online at www.medpharm.tandfonline.com/ojfp) S Afr Fam Pract 2018; DOI: 10.1080/20786190.2017.1364013

MSc (Pharmacology), North-West University, Potchefstroom Campus South Africa has the largest human immunodeficiency virus (HIV) epidemic in the world, with the number of people living with HIV increasing to 7.06 million by mid-2017. In October 2014, the Joint United Nations Programme on HIV/AIDS (UNAIDS) implemented the 90-90-90 targets. This means 90% of people living with HIV should know their HIV status, 90% of people diagnosed with HIV should receive antiretroviral therapy (ART) and 90% of those receiving ART should be virally suppressed by the end of 2020 to end the epidemic as a public threat by 2030. The number of patients experiencing virological failure will inevitably increase due to greater access and prolonged exposure to antiretroviral therapy (ART); this may increase the need for third-line antiretroviral therapy (TLART) in a resource-limited setting such as South Africa. The main overarching aim of this all-inclusive retrospective descriptive investigation was to create a typical clinical profile of adult patients initiated onto TLART in the North West Province of South Africa by reporting and describing the demographics, certain clinical variables and viral resistance patterns recorded from patient health records. Approval to conduct this study was obtained from the North West Department of Health, Policy, Planning, Research, Monitoring and Evaluation Directorate, Mahikeng, on 13 January 2017. Ethics approval was obtained from the North-West University, Health Research Ethics Committee, with approval number NWU-00340-16-A1, on 13 March 2017 with a protocol amendment to replace and add an additional study-site, approved on 25 May 2017. All recorded data were analysed by means of descriptive statistics, with median (interquartile range, IQR: 25th to 75th) used for variables without a normal distribution and percentages (frequencies) used for categorical variables. The Stanford University HIV Drug Resistance Database was used to interpret the clinical significance of drug resistant mutations identified in the study population. Twenty-one adult patients were included in this cohort, 17 were females and four males, located in three districts and four hospitals of the North West Province. The median age at HIV diagnosis was 34 years (IQR: 30.25-36.75) and 46 years (IQR: 40-48.50), respectively, at TLART initiation. At baseline, a median CD4 count and viral load (VL) of 68.50 cells/μL (IQR: 40.75-127.75) and 98 000 copies/ml (IQR: 45 569-820 000), were reported respectively. At failure of first-line ART, the CD4 count and VL were 79.00 cells/ μL (IQR: 26.5-124) and 100 000 copies/ml (IQR: 42 085-248 852), and at the end of second-line ART failure the CD4 count and VL were 119 cells/μL (IQR: 61.25-201.25) and 73 196 copies/ml (IQR: 26 210-197 007), respectively. Clinical monitoring markers documented included, serum creatinine, haemoglobin, mean corpuscular volume (MCV), alanine transferase (ALT) and total cholesterol at baseline and at first- and second-line ART failure. Some of these results, however, were incomplete due to missing data in patient health records, thus drawing any valuable conclusion to contribute to the description of a typical clinical profile was not possible. The median duration from HIV diagnosis to first-line ART initiation was 101 days (IQR: 36.50-366.75), on first-line ART it was 1 269 days (IQR: 765-2 343), on second-line ART 1 512 days (IQR: 706-2 096) and between second-line ART failure and TLART initiation, 71 days (IQR: 57.5-126). The first-line ART regimen, most often initiated was (n=11) lamivudine (3TC), stavudine (d4T) and efavirenz (EFV) which occurred prior to 2010 and the PI-based second-line ART regimen was (n=7) lamivudine (3TC), zidovudine (AZT) and ritonavir boosted lopinavir (LPV/r). The resistance mutations most prevalent for protease inhibitors (PIs) (n=20) were M46I (75%), V82A (65%) and I54V (65%). The median number of total PI resistance mutations (major and minor) found per patient was three mutations (IQR: 2-3). The resistance mutations most prevalent for nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) (n=18) were M184V (89.47%), D67N (31.58%), M41L (26.31%) and T215Y, and V118I (21.05%) and for non-nucleoside reverse transcriptase inhibitors (NNRTIs) (n=17): K103N (47.01%) and G190A (23.52%). High-level of resistance most prevalent in this cohort for PIs were against nelfinavir/r (85.7%), indinavir/r (81.0%), lopinavir/r (76.2%), fosamprenavir/r (66.7%) and atazanavir/r (57.1%); NRTIs were emtricitabine (95.2%), lamivudine (95.2%) and zidovudine (52.4%); NNRTIs were nevirapine (76.2%) and efavirenz (71.4%). A constant low CD4 count and detectable VL >50 copies/mL throughout the duration of ART were found in this study population. The duration between second-line ART failure and TLART initiation found in this study may contribute to an increased number of PI resistance mutations, after a median duration of 71 days (IQR: 58-126). High-level cross-resistance between PIs and a combination of major and minor PI resistant mutations were found in most patients in this study population, but even with limited data numbers, certain markers were identified and used to create an initial clinical profile of the patients. Results from this study can form the basis for larger studies in South Africa, to create more successful TLART management and care programmes. One of the limitations of this retrospective descriptive investigation was the missing data at certain time-points, as the majority of the retrospective data dated back to 2004 and the National ART guidelines changing several times with regards to the regimen compositions, efficacy and toxicity tests and frequencies of monitoring intervals. This study highlighted important demographic and clinical characteristics that may improve the management and care of HIV patients and possibly prevent patients from failing their respective ART regimens. It also highlighted the importance of individualised HIV management and care programs in each healthcare facility, intensified adherence counselling and earlier drug resistance testing for improved and more effective and optimised ART in the future. Masters

South Africa has the highest burden of the human immunodeficiency virus (HIV) infection globally. Efavirenz (EFV), a frequently used drug against HIV infection, displays a relationship between drug concentration and pharmacodynamics effects clinically. However, haplotype-based genetic variation in drug metabolism in a pediatric sample has been little considered in a longitudinal long-term context. CYP2B6 plays a key role in variation of EFV plasma concentration through altered drug metabolism. We report here on a prospective clinical pharmacogenomics/pharmacokinetic study of Bantu-speaking children, importantly, over a period of 24 months post-initiation of EFV-based treatment in South Africa. We characterized the HIV-1-infected children (n = 60) for the CYP2B6 c.516G>T, c.785A>G, c.983T>C, and c.1459C>T single nucleotide polymorphisms (SNPs). These SNPs were determined using polymerase chain reaction/restricted fragment length polymorphism and SNaPshot genotyping. Longitudinal mid-dose EFV plasma concentrations were determined by LC-MS/MS and association analyses with genotypes and haplotypes at 1, 3, and 24 months were performed. The CYP2B6 c.516T/T genotype showed significantly higher EFV plasma concentrations (p T,–c.785A>G and c.983T>C. The haplotype T-G-T presented with significantly increased EFV plasma concentrations compared to the reference G-A-T haplotype at 1, 3, and 24 months (p = 0.009; p = 0.003; p = 0.001), suggesting that the T-G-T haplotype predisposes a risk of EFV plasma concentrations >4 μg/mL. The clinical implications of these pharmacogenomics observations for EFV toxicity and treatment resistance warrant further future research

Background: Tenofovir disoproxil fumarate (TDF) antiretroviral therapy is associated with disruption of the bone turnover process.Objectives: The objective of this study was to determine the association between tenofovir (TFV) plasma concentration and various bone turnover markers and compare these markers in HIV-infected women and HIV-uninfected controls.Method: A cross-sectional sub-study included 30 HIV-infected women on TDF and 30 HIV-uninfected matched participants. Serum calcium (SrCa), serum phosphate (SrP), C-terminal telopeptide (CTx), parathyroid hormone (PTH), alkaline phosphatase (ALP), C-reactive protein (CRP), vitamin D (VitD) and bone mineral density (BMD) were measured. Plasma TFV was assayed on HPLC-MS/MS. The statistical tests applied were Mann–Whitney test, unpaired t-test, analysis of covariance, regression and correlation analysis.Results: In HIV-infected women, no correlation existed between plasma TFV concentration and CTx, PTH, ALP, SrCa, SrP, VitD or BMD (p > 0.05). After adjusting for smoking and alcohol use, ALP (p < 0.001), CTx (p = 0.027) and PTH (p = 0.050) were significantly higher in HIV-infected compared to HIV-uninfected women. Women with TFV concentration ≥ 120 ng/mL had higher PTH concentrations (p = 0.037) compared to those with ≤ 100 ng/mL. Significant correlations between SrCa and PTH and SrCa and SrP including CTx and PTH (p < 0.05) were present in HIV-uninfected women while absent in HIV-infected counterparts (p > 0.05).Conclusion: The results indicate possible increased bone turnover at higher TFV concentrations. The normal regular bone turnover processes in HIV-infected women on TDF therapy are altered. Larger studies are warranted to confirm these results.

A simple, fast and cost-effective method was developed and validated for the determination of levetiracetam (LEV) in plasma/serum of patients using high performance liquid chromatography (HPLC) with ultraviolet detection. The stability of LEV plasma/serum samples over time and in different blood collection tubes was evaluated. Serum/plasma samples were deproteinized by methanol spiked with the internal standard, gabapentin. HPLC was carried out on a Venusil XBP C18, 250 × 4.6 mm, 5 μm column, at a flow rate of 1.0 mL/min and with mobile phase consisting of 50 mm potassium dihydrogen phosphate–acetonitrile at a pH of 5.5. The UV detector was set at 205 nm and 10 μL was injected. Total runtime was 15 min. Calibration curves were linear (correlation coefficient = 0.999) over a concentration range of 1–60 μg/mL. Relative standard deviation values for both the inter-day and intra-day precision and accuracy were

Background: Tenofovir disoproxil fumarate (TDF) has been associated with kidney tubulardys function and reduced renal function. Limited studies were performed in Europe and Asia that related plasma tenofovir (TFV) concentration with renal function; no such studies to date have been performed on Africans. Objective: To investigate the correlation between plasma tenofovir (TFV) concentration and certain renal function markers in HIV-infected women on TDF antiretroviral therapy (ART).These markers were also compared to a HIV-uninfected control group. Methods: HIV-infected women ( n = 30) on TDF-based ART were matched with 30 controls forage and body mass index. Renal markers analysed were estimated glomerular filtration rate (eGFR), creatinine clearance (CrCl), serum creatinine, albuminuria, glucosuria, serum urea, serum uric acid, urine sodium and maximum tubular reabsorption of phosphate. Baseline eGFR and CrCl data were obtained retrospectively for the HIV-infected women. Plasma TFV was assayed using a validated HPLC-MS/MS method. Step wise regression, Mann–Whitney test, unpaired and paired t -tests were applied in the statistical analyses. Results: TFV concentration was independently associated with albuminuria (adjusted r 2 = 0.339; p = 0.001) in HIV-infected women. In the adjusted (weight) analysis, eGFR ( p = 0.038),CrCl ( p = 0.032) and albuminuria ( p = 0.048) were significantly higher in HIV-infected compared to the uninfected women, but eGFR was abnormally high in HIV-infected women. Both eGFR ( p < 0.001) and CrCl ( p = 0.008) increased from baseline to follow-up in HIV-infected women. Conclusion: Plasma TFV concentration was associated with increased albuminuria in HIV infected women in this sub-study. Both eGFR and CrCl were increased in HIV-infected women from baseline. These findings should be confirmed in larger studies, and hyperfiltration in HIV-infected women warrants further investigation.

Therapeutic drug monitoring (TDM) fulfils an important function in patient health in both the public and private healthcare systems. TDM is based on pharmacokinetic principles within the clinical laboratory and several health professionals, from different disciplines, take part in the management and implementation of the whole TDM process. Communication and collaboration between these professionals are extremely important to ensure beneficial TDM and patient care, however, human error plays a major role in the compromising of the TDM process. In this article, we discuss the most common human errors during the TDM process and give guidelines to prevent them. These guidelines must be implemented during all the TDM phases to ensure the patient receives optimal and reliable healthcare

Objective To investigate the influence of CYP2B6 516G>T polymorphism, as a covariate, and of interoccasion variability (IOV) on the oral clearance (CL/F) of efavirenz (EFV) in treatment-naïve black South African children over a period of 24 months post-antiretroviral therapy (ART) initiation. Methods HIV-infected black children (n = 60, aged 3–16 years), with no prior exposure to ART, eligible to commence ART and attending an outpatient clinic were enrolled into this study. Blood samples were taken at mid-dose interval at 1, 3, 6, 12, 18 and 24 months post-ART initiation. EFV plasma samples were determined with an adapted and validated LC/MS/MS method. Genotyping of the CYP2B6 G516T single nucleotide polymorphism (SNP) was performed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). NONMEM was used for the population pharmacokinetic modelling. Results EFV concentrations below 1 μg/mL accounted for 18% (116/649), EFV concentrations >4 μg/mL accounted for 29.5% (192/649) and concentrations within the therapeutic range (1–4 μg/mL) represented 52.5% (341/649) of all the samples determined. The covariates age, weight and CYP2B6 G516Tgenotype were included in the final model with population estimates for CL/F determined as 2.46, 4.60 and 7.33 L/h for the T/T, G/T and G/G genotype groups respectively. Conclusions The inclusion of both age and weight to predict accurate EFV CL values for the respective genotype groups within this paediatric population was required, whereas the addition of gender and body surface area did not improve the predictions. The importance of introducing IOV in a PK model for a longitudinal study with sparsely collected data was again highlighted by this investigation. http://dx.doi.org/10.1007/s00228-011-1148-7

The interaction between verapamil, a P-glycoprotein (P-gp) inhibitor, with ritonavir and lopinavir/ritonavir (LPV/r) after acute and chronic treatment was investigated in rats. Rats were divided into 4 groups, viz. Group 1: ritonavir, 20 mg/kg/d (n=18), group 2: ritonavir, 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18), group 3: LPV/r, 80 and 20 mg/kg/d (n=17) and group 4: LPV/r, 80 and 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18). Blood samples were collected after decapitation on days 1, 7 and 21. Lopinavir and ritonavir plasma levels were simultaneous determined by a validated LC/MS/MS method. The lower limit of quantification for both ritonavir and lopinavir was 0.078 µg/ml. Verapamil significantly increased ritonavir plasma levels, administered as monotherapy, following acute (p