Alison H. Thomson

Aims: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance.Methods: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed‐effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution.Results: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non‐GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug‐specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non‐GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50‐5.69) (gentamicin), 7.77 L/h (95% CI 7.26‐8.19) (amikacin) and 4.70 L/h (95% CI 4.61‐4.80) (vancomycin).Conclusions: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

To evaluate amoxicillin, metronidazole and gentamicin dosage regimens for antibiotic prophylaxis in colorectal surgery. The study was conducted in 20 patients undergoing colorectal surgery. Patients received one or two doses of amoxicillin 1000 mg, metronidazole 500 mg and gentamicin 3 mg/kg ideal body weight, banded by height. Antibiotic concentrations were measured up to 7 h post dose. Population pharmacokinetic (PopPK) analysis with NONMEM followed by Monte Carlo simulation of different dosage regimens was used to estimate the PTA for potential organisms associated with surgical site infections (SSIs). A median of 5 (range 3–6) concentrations were available per patient. CL and V of all antibiotics were related to weight; gentamicin CL was also related to CL_CR. The administered doses maintained the desired PTA up to 8 h for the Streptococcus anginosus group but not for enterococci, Bacteroides fragilis group, MSSA, and Escherichia coli. An additional 500 mg amoxicillin every 4 h was sufficient to achieve the PTA for most relevant organisms but 2 hourly dosing was required for patients at risk of infective endocarditis. A metronidazole dose of 1000 mg was required for patients >85 kg. In patients with CL_CR >50 mL/min, 5 mg/kg gentamicin (with an additional 2.5 mg/kg in prolonged surgery at 6 h) maintained PTA targets for >10 h. PopPK analysis with Monte Carlo simulation identified prophylactic antibiotic regimens that would maintain the PTA for organisms associated with SSIs during short- and long-duration colorectal surgery.

There is limited information on amikacin pharmacokinetics (PK) and dose requirements in patients with mycobacterial infections. To conduct a population PK analysis of amikacin data from patients with mycobacterial infections and compare predicted concentrations from standard and modified dosage guidelines with recommended target ranges. A population PK model was developed using NONMEM. C_max, C_min, concentration 1 h post-infusion (C_1h) and AUC_0–24 using 15 mg/kg daily (once daily), the WHO table, 25 mg/kg three times weekly (TTW) and modified guidelines were compared using Monte Carlo simulations of 1000 patients. Data were available from 124 patients (684 concentrations) aged 16–92 years. CL was 4.64 L/h per 100 mL/min CL_CR; V was 0.344 L/kg. With once-daily regimens, C_max was 35–45 mg/L in 30%–35% of patients and 35–50 mg/L in 46%–48%; C_1h was 25–40 mg/L in 53%–59%. The WHO table produced high C_max values in patients 75 kg. With TTW dosing, around 30% of C_max values were 65–80 mg/L, 40% were 60–80 mg/L, and 48% of C_1h were 45–65 mg/L. Increasing the dosage interval for patients with CL_CR 2 mg/L from 34% to 25% for once-daily dosing and from 18% to 13% for TTW. In patients whose C_min was 0–24 values were 100–300 mg.h/L. Standard amikacin dosing guidelines achieve low percentages of target concentrations for mycobacterial infections. Extending the dosing interval in renal impairment and widening target ranges would reduce the need for dose adjustment.

Background: Scottish Antimicrobial Prescribing Group (SAPG) recommendations to reduce broad-spectrum antimicrobial use led to an increase in gentamicin and vancomycin prescribing. In 2009, SAPG introduced national guidance to standardize dosage regimens, reduce calculation errors and improve the monitoring of these antibiotics. Studies conducted in 2010 and 2011 identified limitations in guideline implementation. Objectives: To develop, implement and assess the long-term impact of quality improvement (QI) resources to support gentamicin and vancomycin prescribing, administration and monitoring. Methods: New resources, comprising revised guidelines, online and mobile app dose calculators, educational material and specialized prescribing and monitoring charts were developed in collaboration with antimicrobial specialists and implemented throughout Scotland during 2013–16. An online survey in 2017 evaluated the use of these resources and a before (2011) and after (2018) point prevalence study assessed their impact. Results: All 12 boards who responded to the survey (80%) were using the guidance, electronic calculators and gentamicin prescription chart; 8 used a vancomycin chart. The percentage of patients who received the recommended gentamicin dose increased from 44% to 89% (OR 10.99, 95% CI = 6.37–18.95) between 2011 and 2018. For vancomycin, the correct loading dose increased from 50% to 85% (OR = 5.69, CI = 2.76–11.71) and the correct maintenance dose from 55% to 90% (OR = 7.17, CI = 3.01–17.07). Conclusions: This study demonstrated improvements in the national prescribing of gentamicin and vancomycin through the development and coordinated implementation of a range of QI resources and engagement with local and national multidisciplinary teams.

Objectives: In Scotland, post-registration hospital pharmacists typically undertake a vocational foundation training programme. Beyond this, there are no mandatory structures for ongoing professional training. To support progression to a more advanced level, competency frameworks are increasingly being used. This study aimed to measure the self-reported competence of pharmacists against a relevant framework and to determine what support was required to enable further professional development. Methods: An online survey was completed by pharmacists working across six acute hospital sites within NHS Greater Glasgow and Clyde who had completed foundation training between Jan 2013 and Jan 2018. Participants self-reported competency against the Royal Pharmaceutical Society's Advanced Practice Framework Advanced Stage 1 competencies and gave qualitative feedback through free-text questions. Key findings: Twenty out of twenty-eight eligible pharmacists (71.4%) responded to the survey and three core areas requiring further support were identified: leadership, management and research. Participants reported that a strategic plan for professional development, more opportunities and managerial support were needed to help them develop these areas. Mentorship programmes and postgraduate qualifications were suggested as formats to support development. Conclusion: Pharmacists working towards advanced practice reported high levels of competence in expert professional practice, collaborative working relationships and education, training and development. While these results are promising, additional support is likely to be needed to cultivate leadership, management and research skills. Future training strategies need to consider this imbalance if we are to achieve national and international workforce goals for the professional development of pharmacists.

To investigate factors affecting aminoglycoside clearance in adult patients with cystic fibrosis who received multiple courses of antibiotic therapy over a period of up to 15 years. Aminoglycoside concentration–time data and relevant clinical characteristics were collated from clinical pharmacokinetic databases established in Glasgow, Scotland and The Hague, The Netherlands. Data from Glasgow (1993–2009) were used for population model development; data from The Hague (2002–11) were used for model validation. NONMEM was used to determine structural and covariate models, with a particular focus on between-occasion variability and changes in aminoglycoside handling over multiple courses of therapy. The Glasgow dataset comprised 1075 courses of aminoglycoside therapy (96% tobramycin and 4% gentamicin) in 166 patients and included 2238 concentration measurements. The data were best described by a two-compartment model with creatinine clearance and height influencing aminoglycoside clearance, and height influencing volume of distribution. Between-subject and between-occasion variabilities in clearance were low, at 18% and 11%, respectively; between-subject variability was 12% for volume of distribution. Internal and external model validations were satisfactory. Multiple courses of therapy (ranging from 2 to 28 courses per patient) were not associated with any systematic changes in aminoglycoside clearance. Height was a better descriptor of aminoglycoside pharmacokinetics than weight in adult patients with cystic fibrosis. No changes in clearance were observed over time, even in patients who had received multiple courses of therapy over several years.

Conducting clinical pharmacology research studies in pediatric patients is challenging because of ethical and practical constraints but necessary to ensure that drugs are used safely and effectively in this population. Developments in laboratory analytical techniques, such as improved assay sensitivity and the use of alternative sample matrices, can reduce blood loss and offer less invasive blood sampling, causing less trauma to the patient and fewer ethical concerns. Recent advances in data analysis techniques, which aim to extract the maximum amount of useful information from small sample numbers, should be considered when planning a clinical trial and incorporated into the study design. Using 'population' methodology allows a more flexible sampling strategy that enables valuable data to be collected in the course of routine clinical practice, rather than in a rigid, and potentially artificial, setting. Integration of pharmacokinetics and pharmacodynamics and the application of physiological approaches and simulation techniques to the analysis and interpretation of drug concentration and effect data offer new opportunities that have particular relevance to pharmacological research in the field of pediatric anesthetics

The long elimination half-life of teicoplanin facilitates outpatient parenteral antibiotic therapy (OPAT) with thrice-weekly dosing. This study aimed to develop teicoplanin dosage guidelines for OPAT use from routine clinical data. Patients received 15–25 mg/kg/day for 3 days, then 15–25 mg/kg thrice weekly. Trough concentrations were measured weekly and doses adjusted to maintain 20–30 or 10–20 mg/L according to clinical condition. Concentration–time data were analysed using the pharmacokinetic package NONMEM and the final model was used to develop new dosage guidelines. Data from 94 and 36 patients were used for model development and validation, respectively. Patient ages ranged from 15 to 94 years, weights from 43 to 146 kg and estimated CL_CR from 9 to 195 mL/min. Teicoplanin concentrations (n = 670) ranged from 6.7 to 66.9 mg/L and a one-compartment model adequately described the data. The typical estimate of CL was 0.542 L/h and changed by 10.6% for every 10 mL/min difference from a CL_CR of 66 mL/min. V was 1.62 L/kg. Dosage guidelines based on body weight and CL_CR can be expected to lead to a significant improvement in the proportion of concentrations in the range 20–30 mg/L. Alternative doses aimed at lower target concentrations have also been developed. New dosage guidelines have been developed to support thrice-weekly administration of teicoplanin in an OPAT setting.

The aims of this study were to develop a population pharmacokinetic model of vancomycin in adult patients, to use this model to develop dosage guidelines targeting vancomycin trough concentrations of 10–15 mg/L and to evaluate the performance of these new guidelines. All data analyses were performed using NONMEM®. A population pharmacokinetic model was first developed from vancomycin dosage and concentration data collected during routine therapeutic drug monitoring in 398 patients, then new vancomycin dosage guidelines were devised by using the model to predict vancomycin trough concentrations in a simulated dataset. Individual estimates of CL and V1 were then obtained in an independent group of 100 patients using the population model and the POSTHOC option. These individual estimates were used to predict vancomycin trough concentrations and steady-state AUC₂₄/MIC ratios using the current and new dosage guidelines. The population analysis found that the vancomycin data were best described using a bi-exponential elimination model with a typical CL of 3.0 L/h that changed by 15.4% for every 10 mL/min difference from a CL_CR of 66 mL/min. V_ss was 1.4 L/kg. The proposed dosage guidelines were predicted to achieve 55% of vancomycin troughs within 10–15 mg/L and 71% within 10–20 mg/L, which is significantly higher than current guidelines (19% and 22%, respectively). The proportion of AUC₂₄/MIC ratios above 400 was also higher, 87% compared with 58%. New vancomycin dosage guidelines have been developed that achieve trough concentrations of 10–15 mg/L earlier and more consistently than current guidelines.