Reinier M. van Hest

A Mycobacterium tuberculosis cluster demonstrating the use of genotyping in urban tuberculosis control.

BackgroundDNA fingerprinting of Mycobacterium tuberculosis isolates offers better opportunities to study links between tuberculosis (TB) cases and can highlight relevant issues in urban TB control in low-endemic countries.MethodsA medium-sized molecular cluster of TB cases with identical DNA fingerprints was used for the development of a visual presentation of epidemiologic links between cases.ResultsOf 32 cases, 17 (53%) were linked to the index case, and 11 (34%) to a secondary case. The remaining four (13%) could not be linked and were classified as possibly caused by the index patient. Of the 21 cases related to the index case, TB developed within one year of the index diagnosis in 11 patients (52%), within one to two years in four patients (19%), and within two to five years in six patients (29%).ConclusionCluster analysis underscored several issues for TB control in an urban setting, such as the recognition of the outbreak, the importance of reinfections, the impact of delayed diagnosis, the contribution of pub-related transmissions and its value for decision-making to extend contact investigations. Visualising cases in a cluster diagram was particularly useful in finding transmission locations and the similarities and links between patients.

A cluster randomized trial for the implementation of an antibiotic checklist based on validated quality indicators: the AB-checklist

BackgroundRecently we developed and validated generic quality indicators that define ‘appropriate antibiotic use’ in hospitalized adults treated for a (suspected) bacterial infection. Previous studies have shown that with appropriate antibiotic use a reduction of 13% of length of hospital stay can be achieved. Our main objective in this project is to provide hospitals with an antibiotic checklist based on these quality indicators, and to evaluate the introduction of this checklist in terms of (cost-) effectiveness.Methods/DesignThe checklist applies to hospitalized adults with a suspected bacterial infection for whom antibiotic therapy is initiated, at first via the intravenous route. A stepped wedge study design will be used, comparing outcomes before and after introduction of the checklist in nine hospitals in the Netherlands. At least 810 patients will be included in both the control and the intervention group. The primary endpoint is length of hospital stay. Secondary endpoints are appropriate antibiotic use measured by the quality indicators, admission to and duration of intensive care unit stay, readmission within 30xa0days, mortality, total antibiotic use, and costs associated with implementation and hospital stay. Differences in numerical endpoints between the two periods will be evaluated with mixed linear models; for dichotomous outcomes generalized estimating equation models will be used. A process evaluation will be performed to evaluate the professionals’ compliance with use of the checklist. The key question for the economic evaluation is whether the benefits of the checklist, which include reduced antibiotic use, reduced length of stay and associated costs, justify the costs associated with implementation activities as well as daily use of the checklist.DiscussionIf (cost-) effective, the AB-checklist will provide physicians with a tool to support appropriate antibiotic use in adult hospitalized patients who start with intravenous antibiotics.Trial registrationDutch trial registry: NTR4872

Nonlinear Mixed Effects Modeling of the Diurnal Blood Pressure Profile in a Multiracial Population

BACKGROUNDnCardiac and cerebrovascular events in hypertensive patients are related to specific features of the 24-hour diurnal blood pressure (BP) profile (i.e., daytime and nighttime BP, nocturnal dip (ND), and morning surge (MS)). This investigation aimed to characterize 24-hour diurnal systolic BP (SBP) with parameters that correlate directly with daytime and nighttime SBP, ND, and MS using nonlinear mixed effects modeling.nnnMETHODSnAmbulatory 24-hour SBP measurements (ABPM) of 196 nontreated subjects from three ethnic groups were available. A population model was parameterized in NONMEM to estimate and evaluate the parameters baseline SBP (BSL), nadir (minimum SBP during the night), and change (SBP difference between day and night). Associations were tested between these parameters and patient-related factors to explain interindividual variability.nnnRESULTSnThe diurnal SBP profile was adequately described as the sum of 2 cosine functions. The following typical values (interindividual variability) were found: BSL = 139 mm Hg (11%); nadir = 122 mm Hg (14%); change = 25 mm Hg (52%), and residual error = 12 mm Hg. The model parameters correlate well with daytime and nighttime SBP, ND, and MS (R (2) = 0.50-0.92). During covariate analysis, ethnicity was found to be associated with change; change was 40% higher in white Dutch subjects and 26.8% higher in South Asians than in blacks.nnnCONCLUSIONSnThe developed population model allows simultaneous estimation of BSL, nadir, and change for all individuals in the investigated population, regardless of individual number of SBP measurements. Ethnicity was associated with change. The model provides a tool to evaluate and optimize the sampling frequency for 24-hour ABPM.

Pharmacokinetic–Pharmacodynamic Modeling of the Antihypertensive Effect of Eprosartan in Black and White Hypertensive Patients

Background and ObjectiveIt is well recognized that many antihypertensive drugs exhibit large interindividual variability in effect and that this wide range of patient response to antihypertensive drugs is a major problem in achieving blood pressure (BP) control. Variability in both drug concentration and drug effect may cause the heterogeneity in antihypertensive drug response. However, for most antihypertensive drugs, no clear relationship between drug concentration and its effect on BP has been reported. This study aimed to describe the relationship between eprosartan exposure and its effect on the systolic blood pressure (SBP) using population pharmacokinetic–pharmacodynamic modeling. Interindividual variability in pharmacokinetics and pharmacodynamics was quantified and the influence of covariates on this relationship was evaluated.Patients and MethodsEprosartan plasma concentrations and SBP measurements were determined in 86 mildly hypertensive patients from the ROTATE study aged 48.1xa0±xa07.6xa0years with different ethnic backgrounds (33 White Dutch, 41 Creole Surinamese, 12 Hindustani Surinamese). In 12 of these patients, pharmacokinetics were densely sampled and 24-h ambulatory BP measurements were obtained. Data were analyzed using nonlinear mixed effects modeling.ResultsEprosartan concentration–time profiles were adequately described with a two-compartment pharmacokinetic model with zero-order absorption. A log-linear relationship was used to describe the relationship between concentration and the decrease in SBP. A hypothetical effect compartment was used to describe hysteresis in the drug effect. Approximately 80xa0% of the maximum decrease in SBP was observed after 24xa0days. Interindividual variability in drug response was 65xa0% and decreased to 14xa0% when ethnicity was added as covariate. Creole Surinamese exhibited no drug response in contrast to White Dutch and Hindustani Surinamese [−2.6xa0mmxa0Hg per (ng/ml)].ConclusionsThe developed pharmacokinetic–pharmacodynamic model allows the quantification and explanation of variability in SBP between individuals with ethnicity as a useful determinant of responsiveness to eprosartan.

Pharmacokinetics and pharmacodynamic target attainment of ceftriaxone in adult severely ill sub-Saharan African patients: a population pharmacokinetic modelling study

BackgroundnIn sub-Saharan Africa (SSA), the highly albumin-bound β-lactam ceftriaxone is frequently used for the empirical treatment of severe bacterial infections. Systemic drug exposure of β-lactams can be altered in critically ill ICU patients, but pharmacokinetic and pharmacodynamic data for non-ICU SSA populations are lacking.nnnMethodsnWe performed a population pharmacokinetic study in an adult hospital population in Mozambique, treated with ceftriaxone for presumptive severe bacterial infection from October 2014 to November 2015. Four blood samples per patient were collected for total ceftriaxone (CEFt) and unbound ceftriaxone (CEFu) concentration measurement. We developed a population pharmacokinetic model through non-linear mixed effect analysis and performed simulations for different patient variable, dosing and pharmacodynamic target scenarios.nnnResultsnEighty-eight participants yielded 277 CEFt and 276 CEFu concentrations. The median BMI was 18.9u2009kg/m2 and the median albumin concentration was 29u2009g/L. In a one-compartment model with non-linear protein binding, creatinine clearance was positively correlated with CEFu clearance. For microorganisms with an MIC of 1u2009mg/L, simulations demonstrated that with a 1u2009g twice-daily regimen and a 2u2009g once-daily regimen, 95.1% and 74.8% would have a CEFu concentrationu2009>u2009MIC during half of the dosing interval (fT>MICu200a=u200a50%), respectively, whereas this was only 58.2% and 16.5% for the fT>MICu200a=u200a100% target.nnnConclusionsnSeverely ill adult non-ICU SSA patients may be at substantial risk for underexposure to CEFu during routine intermittent bolus dosing, especially when their renal function is intact.

Paracetamol clinical dosing routine leads to paracetamol underexposure in an adult severely ill sub-Saharan African hospital population: a drug concentration measurement study

BackgroundHospitals in sub-Saharan Africa (SSA) continue to receive high numbers of severely ill (HIV-infected) patients with physical pain that may suffer from hepatic and renal dysfunction. Paracetamol is widely used for pain relief in this setting but it is unknown whether therapeutic drug concentrations are attained. The aim of this study was to assess the occurrence of therapeutic, sub-therapeutic and toxic paracetamol concentrations in SSA adult hospital population.MethodsIn a cross-sectional study, plasma paracetamol concentrations were measured in patients with an oral prescription in a referral hospital in Mozambique. From August to November 2015, a maximum of four blood samples were drawn on different time points for paracetamol concentration measurement and biochemical analysis. Study endpoints were the percentage of participants with therapeutic (≥xa010 andxa0≤xa020xa0mg/L), sub-therapeutic (<xa010xa0mg/L) and toxic (>xa075xa0mg/L) concentrations.ResultsSeventy-six patients with a median age of 37xa0years, a body mass index of 18.2, a haemoglobin concentration of 10.3xa0g/dL and an albumin of 29xa0g/L yielded 225 samples. 13.4% of participants had one or more therapeutic paracetamol concentrations. 86.6% had a sub-therapeutic concentration at all time points and 70.2% had two or more concentrations below the lower limit of quantification. No potentially toxic concentrations were found.ConclusionsRoutine oral dosing practices in a SSA hospital resulted in substantial underexposure to paracetamol. Palliation is likely to be sub-standard and oral palliative drug pharmacokinetics and dispensing procedures in this setting need further investigation.

Monitoring, documenting and reporting the quality of antibiotic use in the Netherlands: a pilot study to establish a national antimicrobial stewardship registry

BackgroundThe Dutch Working Party on Antibiotic Policy is developing a national antimicrobial stewardship registry. This registry will report both the quality of antibiotic use in hospitals in the Netherlands and the stewardship activities employed. It is currently unclear which aspects of the quality of antibiotic use are monitored by antimicrobial stewardship teams (A-teams) and can be used as indicators for the stewardship registry. In this pilot study we aimed to determine which stewardship objectives are eligible for the envisioned registry.MethodsWe performed an observational pilot study among five Dutch hospitals. We assessed which of the 14 validated stewardship objectives (11 process of care recommendations and 3 structure of care recommendations) the A-teams monitored and documented in individual patients. They provided, where possible, data to compute quality indicator (QI) performance scores in line with recently developed QIs to measure appropriate antibiotic use in hospitalized adults for the period of January 2015 through December 2015ResultsAll hospitals had a local antibiotic guideline describing recommended antimicrobial use. All A-teams monitored the performance of bedside consultations in Staphylococcus aureus bacteremia and the prescription of restricted antimicrobials. Documentation and reporting were the best for the use of restricted antimicrobials: 80% of the A-teams could report data. Lack of time and the absence of an electronic medical record system enabling documentation during the daily work flow were the main barriers hindering documentation and reporting.ConclusionsFive out of 11 stewardship objectives were actively monitored by A-teams. Without extra effort, 4 A-teams could report on the quality of use of restricted antibiotics. Therefore, this aspect of antibiotic use should be the starting point of the national antimicrobial stewardship registry. Our registry is expected to become a powerful tool to evaluate progress and impact of antimicrobial stewardship programs in hospitals.

Pharmacokinetics and Pharmacodynamic Target Attainment of Benzylpenicillin in an Adult Severely ill Sub-Saharan African Patient Population

BackgroundnIn intensive care (ICU) patients, systemic exposure of β-lactam antibiotics can be altered, and positive clinical outcome is associated with increasing fT > MIC ratios. In sub-Saharan African hospitals, benzylpenicillin (PEN) is frequently used for the empiric treatment of severe pneumococcal infections. Pharmacokinetic data for non-ICU hospitalized populations are lacking.nnnMethodsnWe performed a population pharmacokinetic (PPK) study in an adult Mozambican hospital population treated intravenously with PEN from October 2014 through November 2015. Four blood samples/patient were collected for total PEN (PENt) and unbound PEN (PENu) concentration measurement. We developed a PPK model through nonlinear mixed-effects analysis and performed simulations for different patient variable, dosing, and pharmacodynamic target scenarios.nnnResultsnOne hundred twelve participants yielded 387 PENt and 53 PENu concentrations. The median body mass index was 18.3 (range, 10.5-31.3) kg/m2 and the median albumin concentration and creatinine clearance (CrCl) were 29 (range, 12-44) g/L and 80 (range, 3-195) mL/minute, respectively. In a 1-compartment model, CrCl was positively correlated with PENt clearance. For infections with a microorganism with a minimum inhibitory concentration (MIC) of 1 mg/L, simulations demonstrated that with 3 million IU (1.8 g) every 6 hours, 74.1% would have a PENu concentration greater than the MIC during half of the dosing interval (fT > MIC = 50%), whereas this was 24.8% for the fT > MIC = 100% target. For pathogens with an MIC of 0.06 mg/L, these percentages were 98.2% and 72.3%, respectively.nnnConclusionsnSeverely ill adult sub-Saharan African patients may be at high risk for underexposure to PENu during routine intermittent bolus dosing, especially when their renal function is intact and when infected with pathogens with intermediate susceptibility.