Diagnosis, treatment and transmission of rifampicin-resistant TB in the Netherlands, 2010-2019.

BACKGROUND: New tools for diagnosis and treatment of rifampicin-resistant (RR-) and multidrug-resistant (MDR-) TB have become available in the last decade, including better tests confirming transmission.OBJECTIVE: To analyse transmission risks of MDR/RR-TB in the Netherlands.METHODS: Analysis of national data of patients with MDR/RR-TB notified in 2010-2019, including contact investigation and genotyping data.RESULTS: Patients with MDR/RR-TB (n = 121) were more often female (adjusted odds ratio [aOR] 1.5), foreign-born, previously treated for TB (aOR 5.2) and co-infected with HIV (aOR 2.3) than patients with no MDR/RR-TB. Treatment outcomes were satisfactory, with at least 79% completing treatment. After additional whole-genome sequencing (WGS), five molecular clusters of 16 patients remained. Patients in three clusters could not be epidemiologically linked and were unlikely to have been infected in the Netherlands. The remaining eight (6.6%) patients with MDR/RR-TB belonged to two clusters, and were likely the result of transmission in the Netherlands. Among close contacts of patients with smear-positive pulmonary MDR/RR-TB, 13.4% (n = 38) had TB infection and 1.1% (n = 3) had TB disease. Only six contacts with TB infection were treated with a quinolone-based preventive treatment regimen.CONCLUSION: MDR/RR-TB is effectively controlled in the Netherlands. Preventive treatment options could be considered more frequently in contacts clearly infected by an index patient with MDR-TB.

Identifying Features of Cardiac Disease Phenotypes Based on Mechanical Function in a Catecholaminergic Polymorphic Ventricular Tachycardia Model.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by an arrhythmogenic mechanism involving disruption of calcium handling. This genetic disease can lead to sudden death in children and young adults during physical or emotional stress. Prior CPVT studies have focused on calcium handling, but mechanical functionality has rarely been investigated in vitro. In this research we combine stem cell-derived cardiomyocytes from a CPVT patient (RyR2-H2464D mutation) and a healthy familial control with an engineered culture platform to evaluate mechanical function of cardiomyocytes. Substrates with Young's modulus ranging from 10 to 50 kPa were used in conjunction with microcontact printing of ECM proteins into defined patterns for subsequent attachment. Digital Image Correlation (DIC) was used to evaluate collections of contracting cells. The amplitude of contractile strain was utilized as a quantitative indicator of functionality and disease severity. We found statistically significant differences: the maximum contractile strain was consistently higher in patient samples compared to control samples on all substrate stiffnesses. Additionally, the patient cell line had a statistically significantly slower intrinsic contraction rate than the control, which agrees with prior literature. Differences in mechanical strain have not been previously reported, and hypercontractility is not a known characteristic of CPVT. However, functional changes can occur as the disease progresses, thus this observation may not represent behavior observed in adolescent and adult patients. These results add to the limited studies of mechanical function of CPVT CMs reported in literature and identify functional differences that should be further explored.

Modelling cost-effective clearing solutions for invasive alien trees: A case study on wilding conifers.

Accurate on-site identification of appropriate alien clearing methods can realize significant cost savings for heterogenous sites. We developed a cost-based model accounting for site parameters such as infestation density, slope, obstructive vegetation density and site-access. These parameters are combined with a unit-costing sub-module to identify the most cost-effective clearing method for a particular site. The model was tested in the heterogenous Cape Fynbos biome of South Africa for three clearing methods for Pinus: traditional felling, drill-and-fill, and the arial-basal bark application (ABBA) method. The model accounts for the above-mentioned site parameters after which it is calibrated with the unit-costing for each method. Various scenarios consisting of different combinations of above-mentioned site parameters are then applied to identify the cost-effective solution for any particular combination of site parameters. Results favoured the drill-and-fill method in most cases, with the ABBA method reserved for sites with isolated Pines situated in dense fynbos with difficult access at slope gradients of 45° and higher. At these site combinations, ground teams experience longer walk times which reduces their productivity to such an extent that ABBA is comparatively more cost-effective. Traditional felling turned out to be prohibitively expensive because of team composition (mandatory higher safety and supervision requirements required for chainsaw operations) and slower on-site walking due to heavier equipment. The information enables site managers to do more accurate planning since the model will ensure that a cost-effective method is chosen for any particular site. It is then up to the manager to implement the chosen clearing method in a cost-efficient way.

Corrigendum to 'Should treatment of low-level rifampicin mono-resistant tuberculosis be different?' [JCTUBE 23 (2021) 100241].

[This corrects the article DOI: 10.1016/j.jctube.2021.100241.].

Ethnic disparities in tuberculosis incidence and related factors among indigenous and other communities in ethnically diverse Suriname.

BACKGROUND: In Suriname, a country home to many ethnic groups, a high incidence of tuberculosis (TB) has been found among Indigenous Trio Amerindians. However, whether wider ethnic disparities in TB incidence and its associated risk factors (e.g., diabetes mellitus and HIV) exist in Suriname, is not known. We sought to investigate disparities in TB incidence and its risk factors on ethnicity in Suriname, as this could give way to targeted TB intervention programs. METHODS: Anonymized patient data from 2011 to 2015 was extracted from the National TB Registry and analyzed. Differences in the five-year incidence rates of TB for the six largest ethnic groups-Creole, Hindustani, Indigenous, Javanese, Maroon, and Mixed-were assessed using a chi-square goodness-of-fit test, and TB patient differences regarding ethnicity were evaluated for selected factors using a multinomial logistic regression with Creole patients as reference. RESULTS: 662 Patients were eligible for analyses with the following ethnic makeup: Creole (36.4%), Hindustani (15.6%), Indigenous (8.6%), Javanese (10.6%), Maroon (15.1%), and Mixed ethnicity (13.7%). Differences in five-year incidence rates for TB were significant, χ 2(5, N = 662) = 244.42, p < .001, and the highest TB rates were found for Indigenous (280 per 100,000) and Creole people (271 per 100,000). HIV coinfection was a TB risk factor for Creoles (38.2% of these patients were HIV positive). Several variables (i.e., those for drug use) had high levels of incomplete or missing data. CONCLUSIONS: Our study has demonstrated that ethnic disparities in tuberculosis incidence exist in Suriname and that they are associated with specific, known risk factors such as HIV (especially for Creole people). For Indigenous people, risk factors may include diminished access to health care facilities and low socioeconomic status. However, direct data on these factors was unavailable. These findings call for targeted national intervention programs-with special attention given to the vulnerabilities of susceptible ethnic groups-and improved data collection.

Should treatment of low-level rifampicin mono-resistant tuberculosis be different?

BACKGROUND: Rifampicin resistant tuberculosis (RR-TB) was frequently detected in Suriname after the introduction of Xpert MTB/RIF in 2012. Subsequent phenotypic drug-susceptibility testing (DST) was not conclusive at that moment, while RR-TB patients treated with first-line tuberculostatics had good treatment outcome. In our study, we analysed this interesting observation. METHODS: We collected demographic and clinical characteristics and treatment outcome of TB patients from May 2012-December 2018 and performed a univariate and multivariate analysis to assess possible associations with resistance to rifampicin. Secondly, we conducted whole genome sequencing on all available Mycobacterium tuberculosis isolates that had a rifampicin resistance in the Xpert MTB/RIF test and performed phenotypic DST on selected isolates. FINDINGS: RR-TB was detected in 59 (9.6%) patients confirmed by Xpert. These patients were treated with rifampicin-containing regimens in most (88%) of the cases. In all 32 samples examined, a D435Y mutation in the rpoB gene was identified; only one isolate revealed an additional isoniazid mutation. Phenotypic DST indicated low-level rifampicin resistance. In multivariate analysis, the Creole ethnicity was a factor associated with rifampicin resistance (aOR 3.5; 95%CI 1.9-6.4). The treatment success rate for patients with RR-TB (78.0%) was comparable to the treatment outcome in non-RR-TB patients 77.8%. INTERPRETATION: This study confirms a low-level rifampicin mono-resistance in TB patients of Suriname. These patients could benefit from a first-line regimen with high dose rifampicin (or rifabutin), rather than from the lengthy treatment regimens for rifampicin-resistant and multi-drug resistant TB, a concept of stratified medicine also advocated for the treatment of TB. FUNDING: None.

A framework for selecting crops for irrigation using mining contaminated water: An example from the Olifants basin of South Africa.

Irrigated agriculture is adapting to viability challenges due to water contamination from mining in various ways. We explore the option of using crops that are able to tolerate the impacts of such water contamination as a short term adaptation strategy. We present a framework which enables the selection of crops suitable for irrigated production using mining contaminated water. The framework identifies key factors that should inform crop selection; and these include crop adaptation to climatic conditions, contaminants present in water, crop tolerance to contaminants, crop use and accumulation of toxic metals. A proposed process for screening and selecting a crop is described. Although considered a partial analysis due to incomplete and non-standardised information on crop tolerance levels, the framework narrows down choices which can be assessed in more detail or with field trials. The framework shows that interventions beyond the farm level are necessary to support the use of contaminant tolerant crops as a strategy for adapting to water contamination from mining. However, key questions regarding the risks associated with alternative crops and difficulties in selecting suitable crops remain.

A Method to Create a Horizontal Resistance Layer by Injection of a Viscous Fluid: PLAID.

We present a method to create a horizontal resistance layer at desired depth below soil surface to decrease seepage over a relatively large area. The layer is produced in a continuous process by means of numerous temporary screens of wells. Between each pair of screens groundwater flow is forced in horizontal direction. In the center of such flow, along virtual parallel flow lines, a chemical, viscous and dense fluid is injected that produces a clogging substance within several hours. The impact of density is overcome by the forced flow between screens. The impact of viscosity on the flow distribution is handled by adaptation of the fluxes and heads at the filters in the screens. The resulting procedure includes multistep injection and is supported by model simulations. Though a small-scale proof of concept has been successful, the composition of the optimal chemical mixture needs further research.

Pharmacokinetics of 2,000 Milligram Ertapenem in Tuberculosis Patients.

Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC0-∞) was 2,032 (1,751 to 2,346) mg · h/liter, the intercompartmental clearance (CL12) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment (V1) was 1.514 (1.064 to 2.210) liters. A more than dose-proportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time (f40% T>MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f40% T>MIC for most of the patients, and exploration in a phase 2 study can be advocated.

In Vitro Susceptibility of Mycobacterium tuberculosis to Amikacin, Kanamycin, and Capreomycin.

Amikacin, kanamycin, and capreomycin are among the most important second-line drugs for multidrug-resistant tuberculosis. Although amikacin and kanamycin are administered at the same dose and show the same pharmacokinetics, they have different WHO breakpoints, suggesting that the two drugs have different MICs. The aim of this study was to investigate possible differences in MICs between the aminoglycosides and capreomycin. Using the direct concentration method, a range of concentrations of amikacin, kanamycin, and capreomycin (0.25, 0.50, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0, and 64.0 mg/liter) were tested against 57 clinical Mycobacterium tuberculosis strains. The 7H10 agar plates were examined for mycobacterial growth after 14 days. At 2 mg/liter, 48 strains (84%) were inhibited by amikacin and only 5 strains (9%) were inhibited by kanamycin (P < 0.05, Wilcoxon signed-rank test). The median MICs of amikacin, kanamycin, and capreomycin were 2, 4, and 8 mg/liter, respectively. No difference in amikacin, kanamycin, and capreomycin MIC distributions was observed between multidrug-resistant strains and fully susceptible strains. The results indicate that amikacin is more active than kanamycin and capreomycin against M. tuberculosis with the absolute concentration method. Determination of the impact of this difference on clinical outcomes in daily practice requires a prospective study, including pharmacokinetic and pharmacodynamic evaluations.

Towards a rapid assessment protocol for identifying pit lakes worthy of restoration.

Before the introduction of reclamation legislation in South Africa, final cut lakes in mining areas were left without any restoration while the final excavation was not back filled. Characteristics of these lacustrine water bodies vary considerably, but they are often linear in shape, large (1-30 ha), deep (2-30 m) and have poorly developed littoral zones. With water tables often near the surface; a variety of vascular hydrophytes can colonize these bodies, thus establishing emerging wetland type ecosystems. These, man-made aquatic structures that are (unintentionally) created potentially offers some realistic and inexpensive mitigation options for some of the negative impacts associated with mining, i.e. these water bodies can become useful by yielding potentially valuable services. However, no method currently exists to compare and rank these water bodies according ecological integrity and the expected monetary value to be derived from them in order to select sites for restoration. To answer this need, we applied an index to determine the ability of these water bodies to provide useful services in their current state. The index was then used to derive estimates of the monetary value of potential services in order to allow comparison with the cost of restoring the water body in question or to compare with other pit lakes. We present a South African case study to illustrate the method. As far as could be established, this is the first attempt towards creating a rapid assessment tool as standardised way of comparing pit lakes that allows for the ranking and identification of those pit lakes worthy of restoration.

Pharmacokinetic Modeling and Limited Sampling Strategies Based on Healthy Volunteers for Monitoring of Ertapenem in Patients with Multidrug-Resistant Tuberculosis.

Ertapenem is a broad-spectrum carbapenem antibiotic whose activity against Mycobacterium tuberculosis is being explored. Carbapenems have antibacterial activity when the plasma concentration exceeds the MIC at least 40% of the time (40% TMIC). To assess the 40% TMIC in multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on data for healthy volunteers. A two-compartment population pharmacokinetic model was developed with data for 42 healthy volunteers using an iterative two-stage Bayesian method. External validation was performed by Bayesian fitting of the model developed with data for volunteers to the data for individual MDR-TB patients (in which the fitted values of the area under the concentration-time curve from 0 to 24 h [AUC0-24, fit values] were used) using the population model developed for volunteers as a prior. A Monte Carlo simulation (n = 1,000) was used to evaluate limited sampling strategies. Additionally, the 40% TMIC with the free fraction (f 40% TMIC) of ertapenem in MDR-TB patients was estimated with the population pharmacokinetic model. The population pharmacokinetic model that was developed was shown to overestimate the area under the concentration-time curve from 0 to 24 h (AUC0-24) in MDR-TB patients by 6.8% (range, -17.2 to 30.7%). The best-performing limited sampling strategy, which had a time restriction of 0 to 6 h, was found to be sampling at 1 and 5 h (r2 = 0.78, mean prediction error = -0.33%, root mean square error = 5.5%). Drug exposure was overestimated by a mean percentage of 4.2% (range, -15.2 to 23.6%). When a free fraction of 5% was considered and the MIC was set at 0.5 mg/liter, the minimum f 40% TMIC would have been exceeded in 9 out of 12 patients. A population pharmacokinetic model and limited sampling strategy, developed using data from healthy volunteers, were shown to be adequate to predict ertapenem exposure in MDR-TB patients.

Towards tradable permits for filamentous green algae pollution.

Water pollution permit systems are challenging to design and implement. Operational systems that has maintained functionality remains few and far between, particularly in developing countries. We present current progress towards developing such a system for nutrient enrichment based water pollution, mainly from commercial agriculture. We applied a production function approach to first estimate the monetary value of the impact of the pollution, which is then used as reference point for establishing a reserve price for pollution permits. The subsequent market making process is explained according to five steps including permit design, terms, conditions and transactional protocol, the monitoring system, piloting and implementation. The monetary value of the impact of pollution was estimated at R1887 per hectare per year, which not only provide a "management budget" for filamentous green algae mitigation strategies in the study area, but also enabled the calculation of a reserve price for filamentous green algae pollution permits, which was estimated between R2.25 and R111 per gram filamentous algae and R8.99 per gram at the preferred state.

Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis.

For treatment of multidrug-resistant tuberculosis (MDR-TB), there is a scarcity of antituberculosis drugs. Co-trimoxazole is one of the available drug candidates, and it is already frequently coprescribed for TB-HIV-coinfected patients. However, only limited data are available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of co-trimoxazole in TB patients. The objective of this study was to evaluate the PK parameters and in vitro PD data on the effective part of co-trimoxazole: sulfamethoxazole. In a prospective PK study in patients infected with drug-susceptible Mycobacterium tuberculosis (drug-susceptible TB patients) (age, >18), sulfamethoxazole-trimethoprim (SXT) was administered orally at a dose of 960 mg once daily. One-compartment population pharmacokinetic modeling was performed using MW\Pharm 3.81 (Mediware, Groningen, The Netherlands). The area under the concentration-time curve for the free, unbound fraction of a drug (ƒAUC)/MIC ratio and the period in which the free concentration exceeded the MIC (fT > MIC) were calculated. Twelve patients received 960 mg co-trimoxazole in addition to first-line drugs. The pharmacokinetic parameters of the population model were as follows (geometric mean ± standard deviation [SD]): metabolic clearance (CLm), 1.57 ± 3.71 liters/h; volume of distribution (V), 0.30 ± 0.05 liters · kg lean body mass(-1); drug clearance/creatinine clearance ratio (fr), 0.02 ± 0.13; gamma distribution rate constant (ktr_po), 2.18 ± 1.14; gamma distribution shape factor (n_po), 2.15 ± 0.39. The free fraction of sulfamethoxazole was 0.3, but ranged between 0.2 and 0.4. The median value of the MICs was 9.5 mg/liter (interquartile range [IQR], 4.75 to 9.5), and that of theƒAUC/MIC ratio was 14.3 (IQR, 13.0 to 17.5). The percentage of ƒT > MIC ranged between 43 and 100% of the dosing interval. The PK and PD data from this study are useful to explore a future dosing regimen of co-trimoxazole for MDR-TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01832987.).

Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Limited sampling strategies for therapeutic drug monitoring of amikacin and kanamycin in patients with multidrug-resistant tuberculosis.

Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population pharmacokinetic (PPK) model may help to optimise drug exposure. Patients with MDR-TB who had received amikacin or kanamycin as part of their treatment and who had routinely received therapeutic drug monitoring were evaluated. A PPK model was developed and subsequently validated. Using this model, a limited sampling model was developed. Eleven patients receiving amikacin and nine patients receiving kanamycin were included in this study. The median observed 24-h area under the concentration-time curve (AUC0-24h) was 77.2 mg h/L [interquartile range (IQR) 64.7-96.2 mg h/L] for amikacin and 64.1 mg h/L (IQR 55.6-92.1 mg h/L) for kanamycin. The PPK model was developed and validated using n-1 cross-validation. A robust population model was developed that is suitable for predicting the AUC0-24h of amikacin and kanamycin. This model, in combination with the limited sampling strategy developed, can be used in daily routine to guide dosing but also to assess AUC0-24h in phase 3 studies.

Highly successful treatment outcome of multidrug-resistant tuberculosis in the Netherlands, 2000-2009.

SETTING: Resistance to the two key anti-tuberculosis drugs isoniazid and rifampicin is a characteristic of multidrug-resistant tuberculosis (MDR-TB). MDR-TB is a scourge requiring toxic, prolonged treatment and is associated with poor outcomes. The Netherlands is a country with a long-standing, integrated, well-resourced TB service where all patients are offered culture-confirmed diagnosis by a central reference laboratory. OBJECTIVE: To assess the treatment outcomes of MDR-TB patients over a period of 10 years in The Netherlands. DESIGN: Demographic, clinical and microbiological features of all patients with MDR-TB who started treatment in 2000-2009 in the Netherlands were analysed from national registry and patient records. RESULTS: Characteristics of the 113 MDR-TB patients were as follows: male/female ratio 1.57, 96% foreign born, median age 29 years, 96 (85%) pulmonary TB, 56 (50%) smear-positive, 14 (12%) human immunodeficiency virus (HIV) co-infected. Of the 104 (92%) patients who started MDR-TB treatment, 86% had a successful outcome using a median of six active drugs; eight underwent pulmonary surgery. HIV negativity was associated with successful outcome (adjusted OR 2.1, 95%CI 1.1-3.8). CONCLUSION: High success rates for MDR-TB treatment were achieved with close collaboration of all stakeholders, reaching the targets set for drug-susceptible TB. HIV remained an independent risk factor for unsuccessful treatment outcome.