First-line Tuberculosis Drugs Research Articles

The burden of drug resistance tuberculosis in Ghana; results of the First National Survey

Resistance to Tuberculosis drugs has become a major threat to the control of tuberculosis (TB) globally. We conducted the first nation-wide drug resistance survey to investigate the level and pattern of resistance to first-line TB drugs among newly and previously treated sputum smear-positive TB cases. We also evaluated associations between potential risk factors and TB drug resistance. Using the World Health Organization (WHO) guidelines on conducting national TB surveys, we selected study participants from 33 health facilities from across the country, grouped into 29 clusters, and included them into the survey. Between April 2016 and June 2017, a total of 927 patients (859 new and 68 previously treated) were enrolled in the survey. Mycobacterium tuberculosis complex (MTBC) isolates were successfully cultured from 598 (65.5%) patient samples and underwent DST, 550 from newly diagnosed and 48 from previously treated patients. The proportion of patients who showed resistance to any of the TB drugs tested was 25.2% (95% CI; 21.8–28.9). The most frequent resistance was to Streptomycin (STR) (12.3%), followed by Isoniazid (INH) (10.4%), with Rifampicin (RIF), showing the least resistance of 2.4%. Resistance to Isoniazid and Rifampicin (multi-drug resistance) was found in 19 (3.2%; 95% CI: 1.9–4.9) isolates. Prevalence of multidrug resistance was 7 (1.3%; 95% CI: 0.5–2.6) among newly diagnosed and 12 (25.0%; 95% CI: 13.6–39.6) among previously treated patients. At both univariate and multivariate analysis, MDR-TB was positively associated with previous history of TB treatment (OR = 5.09, 95% CI: 1.75–14.75, p = 0.003); (OR = 5.41, 95% CI: 1.69–17.30, p = 0.004). The higher levels of MDR-TB and overall resistance to any TB drug among previously treated patients raises concerns about adherence to treatment. This calls for strengthening existing TB programme measures to ensure a system for adequately testing and monitoring TB drug resistance.

Population Pharmacokinetic Analyses of Isoniazid in Tuberculosis Treatment: a Systematic Review

The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of isoniazid (INH) and to identify factors influencing INH pharmacokinetic variability. Pubmed and Embase databases were systematically searched from inception to July, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of INH written in English, conducted in human (either healthy subjects or pulmonary tuberculosis patients) were included in this review. Ten studies were included in this review. Most studies characterized a two-compartment model with first-order kinetics for INH with a transit-compartment model for absorption suggested. Frequently reported significant predictors for INH clearance is NAT2 acetylator types (slow/intermediate/fast), while weight is a significant covariate for INH volume of distribution (both central and peripheral). In children, enzyme maturation had a profound affect on INH clearance.
 Keywords:
 Population pharmacokinetics, Isoniazid.
 References
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The promises and limitations of N-acetylcysteine as a potentiator of first-line and second-line tuberculosis drugs.

N-acetylcysteine (NAC) is most commonly used for the treatment of acetaminophen overdose and acetaminophen-induced liver injury. In patients infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), NAC is given to treat hepatotoxicity induced by TB drugs. We had previously shown that cysteine, a derivative of NAC, potentiated the activity of isoniazid, a first-line TB drug, by preventing the emergence of INH resistance and persistence in M. tuberculosis in vitro. Herein, we demonstrate that in vitro, NAC has the same boosting activity with various combinations of first- and second-line TB drugs against drug-susceptible and multidrug-resistant M. tuberculosis strains. Similar to cysteine, NAC increased M. tuberculosis respiration. However, in M. tuberculosis-infected mice, the addition of NAC did not augment the activity of first- or second-line TB drugs. A comparison of the activity of NAC combined with TB drugs in murine and human macrophage cell lines revealed that studies in mice might not be recapitulated during host infection in vivo.

Preparation of Curdlan sulphate - Chitosan nanoparticles as a drug carrier to target Mycobacterium smegmatis infected macrophages

In this study, curdlan sulphate - chitosan nanoparticles were prepared through polyelectrolyte complexing at a mass ratio of 2:1 respectively. The curdlan was produced by fermentation with Agrobacterium sp. ATCC 31750, which was then sulphated to form the polyanionic polymer. A first-line tuberculosis drug, Rifampicin and a phytochemical, DdPinitol, were encapsulated into Curdlan Sulphate (CS) - Chitosan Nanoparticles (C) (CSC NPs) of size 205.41 ± 7.24 nm. The drug release kinetics followed a Weibull model with initial burst release (48 % Rifampicin and 27 % d-Pinitol within 6 h), followed by a sustained release. The prepared CSC: d-PIN + RIF NPs was cytocompatible and entered the M.smegmatis infected macrophages through multiple endocytic pathways including clathrin, caveolae and macropinocytosis. They showed superior bactericidal activity (2.4–2.7 fold) within 4 h when compared to free drug Rifampicin (1.6 fold). The drug encapsulated CSC: RIF suppressed the pro-inflammatory gene (TNF-α by 3.66 ± 0.19 fold) and CSC: d-PIN + RIF increased expression of the anti-inflammatory gene (IL-10 by 13.09 ± 0.47 fold). Expression of TGF- β1 gene also increased when treated with CSC: d-PIN + RIF (13.00 ± 0.19 fold) which provided the immunomodulatory activity of the encapsulated CSC NPs. Thus, curdlan sulphate - chitosan polyelectrolyte complex can be a potential nanocarrier matrix for intracellular delivery of multiple drugs.

Type I interferon signaling mediates Mycobacterium tuberculosis-induced macrophage death.

Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN-mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.

Retrospective record review of pregnant women treated for rifampicin-resistant tuberculosis in South Africa.

Tuberculosis (TB) is amongst the top five causes of death in women of childbearing age (15-≤44 years). Little is known about treatment of pregnant women with drug-resistant TB (DR-TB). Treatment for pregnant women remains challenging and more complex in DR-TB/HIV co-infection, where an evidence-based guide to clinical practice is limited. The study reviewed treatment and pregnancy outcomes and birth outcomes of their new-born in a cohort of pregnant women with DR-TB from three MDR-TB hospitals during 2010 and 2018. Data were extracted from: TB register and patient clinic notes using a standardized case record form. Information on DR-TB treatment, pregnancy and Adverse Drug Events (ADEs) of twenty-six pregnant women treated with individualized second-line TB medications were captured. The frequency of favourable and adverse outcomes regarding disease and pregnancy were evaluated. The mean age was 29 years (SD ±5.1), with the minimum and maximum age of 21 and 40 years, respectively. Eleven (42.3%) were previously treated with first-line TB drugs, 11 (42.3%) never treated before and 4 (15.4%) were previously treated for DR-TB. Of the 26 women, 15 (57.7%) had at least one ADE, but most had more than one ADE. Seventeen women were successfully treated, and 22 live births recorded. Live birth outcome was significantly associated with trimester of initiation of DR-TB treatment (p = 0.036). The proportion of live births for the pregnancy trimester when DR-TB treatment was initiated, were 60.0%, 90.9% and 100.0%, for first, second and third trimester, respectively. DR-TB treatment should be delayed until after the first trimester. Routine pharmacovigilance surveillance integrated antenatal and delivery services with an integrated record of DR-TB treatment during pregnancy is recommended. Prospective studies using standardised case record forms for DR-TB treatment for pregnant women could provide more insight on the effect of DR-TB treatment on the birth outcome.

A retrospective study of tuberculosis prevalence amongst patients attending a tertiary hospital in Riyadh, Saudi Arabia

Tuberculosis (TB) is a public health challenge that affects all genders and age groups and is a single leading infectious disease killer globally. We retrospectively investigated the prevalence of TB and anti-TB drug resistance among patients treated at the Prince Sultan Military Medical City (PSMMC) between the years 2000 and 2017. Patient demographic variables and drug susceptibility test results were obtained from TB notification records located in the TB laboratory at PSMMC. A total of 58,141 records were reviewed of which 1123 (2%) specimens were positive for Mycobacterium tuberculosis. Of the positive, 621 (55%) were from pulmonary specimens. Males over the age of 15 years accounted for 60% of the positive specimens. Drug resistance to at least one drug was detected in 90 (8%) of which 60 (5.3%), 24 (2%) 6 (0.5%) patients were mono-drug-resistant, poly-drug resistant and multidrug resistant (MDR-TB) respectively. Resistance to isoniazid and streptomycin were the most frequently found among first-line tuberculosis drugs, accounting for 4.5% and 3.8% of drug resistance cases respectively. Our findings show low prevalence of tuberculosis and multidrug resistant TB among patients treated at PSMMC over a 17-year period. Nationwide assessment is needed to get a clear picture of the TB burden across Saudi Arabia and inform national policies for eradication of TB.

Intestinal microbiota disruption limits the isoniazid mediated clearance of Mycobacterium tuberculosis in mice.

Tuberculosis (TB) continues to remain a global threat due to the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains and toxicity associated with TB drugs. Intestinal microbiota has been reported to affect the host response to immunotherapy and drugs. However, how it affects the potency of first-line TB drug isoniazid (INH) is largely unknown. Here, we examined the impact of gut microbial dysbiosis on INH efficiency to kill Mtb. In this study, we employed in vivo mouse model, pretreated with broad-spectrum antibiotics (Abx) cocktail to disrupt their intestinal microbial population prior to Mtb infection and subsequent INH therapy. We demonstrated that microbiota disruption results in the impairment of INH-mediated Mtb clearance, and aggravated TB-associated tissue pathology. Further, it suppressed the innate immunity and reduced CD4 T-cell response against Mtb. Interestingly, a distinct shift of gut microbial profile was noted with abundance of Enterococcus and reduction of Lactobacillus and Bifidobacterium population. Our results show that the intestinal microbiota is crucial determinant in efficacy of INH to kill Mtb and impacts the host immune response against infection. This work provides an intriguing insight into the potential links between host gut microbiota and potency of INH.

Gene expression tryptophan aspartate coat protein in determining latent tuberculosis infection using immunocytochemistry and real time polimerase chain reaction.

BackgroundTuberculosis (TB) remains a major cause of morbidity and mortality worldwide. Problem of Latent Tuberculosis Infection (LTBI) is increasing in number especially in countries with high TB incidence rate, such as Indonesia. Although not every LTBI will become active TB, if untreated and not handled appropriately it can still be a source of transmission and may increase the rate of resistance to the first-line TB drugs. Mycobacterium tuberculosis as a cause of tuberculosis disease is an intracellular pathogens that survives within the phagosome of host macrophages. Several host factors are involved in this process, including the Tryptophan Aspartate-containing Coat Protein (TACO). TACO is a protein recruited and retained by viable Mycobacterium tuberculosis on the surface of the phagosome membrane to maintain its survival in phagosome, because the presence of TACO plays an important role in inhibiting the fusion of phagosomes and lysosomes.Objectivethe aim of this studyis to assess the difference of gene expression TACO protein in Latent Tuberculosis Infection (LTBI) and healthy people.MethodA preliminary studyof mRNA examination of TACO protein using Immunocytochemistry (ICC) and Real Time-Polimerase Chain Reaction (RT-PCR) method by a PCR Light Cycler 2.0 machine (Roche) in LTBI and healthy groups.Results18 samples of peripheral blood monocyte cells (PBMCs) were collected and divided into 2 groups. We found that there was a significantly difference between the 2 groups of samples.ConclusionFurther research is required to consider that the measurement of TACO expression using RT-PCRcan used as one of the other method to determine LTBI.

Influence of age, sex and hospitalisation on the administration of tuberculosis medication: an evaluation of routine data from a German health insurer.

BackgroundSo far, there is no reliable information on the drugs actually taken by tuberculosis patients. With billing data from a large German health insurance company, valid data from practice will be used for analysis. The objective here is to use the claims data of a health insurer to gain an insight into the prescriptions issued to patients with tuberculosis in Germany.MethodsThe study design encompasses a longitudinal, analytical observational study of selected insurance holders. Descriptive analyses of the outpatient drug supply of pulmonary tuberculosis patients are determined for 6 payroll years. We have studied whether different doses of tuberculosis medication are associated with age, sex, inpatient status and comorbidity. Quantile regression is used as a method to identify subgroups or characteristic dosages.ResultsThe number of defined daily doses prescribed per patient varies among insurance holders and encompasses widely differing timeframes. Higher doses are observed with increasing age, as well as in patients with tuberculosis-related hospitalisations. The sex of the patient has no identifiable effect on the prescribed doses for any of the first-line tuberculosis drugs. Comorbidity partially has a significant impact on the duration and intensity of tuberculosis drug prescriptions.

Pyrazinamide triggers degradation of its target aspartate decarboxylase

Pyrazinamide is a sterilizing first-line tuberculosis drug. Genetic, metabolomic and biophysical analyses previously demonstrated that pyrazinoic acid, the bioactive form of the prodrug pyrazinamide (PZA), interrupts biosynthesis of coenzyme A in Mycobacterium tuberculosis by binding to aspartate decarboxylase PanD. While most drugs act by inhibiting protein function upon target binding, we find here that pyrazinoic acid is only a weak enzyme inhibitor. We show that binding of pyrazinoic acid to PanD triggers degradation of the protein by the caseinolytic protease ClpC1-ClpP. Thus, the old tuberculosis drug pyrazinamide exerts antibacterial activity by acting as a target degrader, a mechanism of action that has recently emerged as a successful strategy in drug discovery across disease indications. Our findings provide the basis for the rational discovery of next generation PZA.

Antibiotic sensitivity of Mycobacterium tuberculosis isolates; a retrospective study from a Saudi tertiary hospital.

ObjectivesThis study aims to examine the antibiotic sensitivity of Mycobacterium tuberculosis isolates and its drug resistance. We also evaluated the relationship between demographic characteristics and tuberculosis (TB) drug susceptibilities.MethodsA retrospective study was conducted to analyse the antibiotic sensitivity of M. tuberculosis isolates and its resistance to first-line anti-TB drugs. During the period 2008–2013, the medical records of 191 patients from the TB ward and the Out-Patient Department in an Eastern KSA tertiary hospital were reviewed.ResultsWe classified the specimens into two categories: extra-pulmonary and pulmonary TB. Among the extra-pulmonary TB specimens, 36.5% were from body fluids, 29.2% from tissue cultures and 5.2% from body abscesses. In case of pulmonary TB, sputum samples accounted for the highest proportion of the specimens (28.6%), followed by bronchial aspirates and pleural fluid (13.2% and 5.7%, respectively). Clinical isolates from women showed higher resistance to ethambutol compared to those from men. Isoniazid showed the highest resistance pattern among all antibiotics tested (17%). Meanwhile, tissue cultures had higher resistance to Isoniazid antibiotic compared to the other specimens.ConclusionResistance to first-line TB drugs is higher in extra-pulmonary TB isolates than pulmonary isolates. Nearly one-fourth of all M. tuberculosis clinical strains were resistant to the antibiotics tested in mono-resistant or multi-resistant manners. Women had greater resistance to TB drug ethambutol as compared to men. Meanwhile, extra-pulmonary TB specimens, specifically that from tissue cultures, showed greater resistance to Isoniazid than other clinical specimens.

Trend of antitubercular drug sensitivity test at a multispecialty hospital in Western India - A Retrospective Analysis

Context: Tuberculosis (TB) infection is still a major public health burden in India. India accounts for about 25% of the global TB burden. Worldwide India is the country with highest burden of both TB and multidrug-resistant (MDR) TB. Aim: The aim of this study was to evaluate the pattern of resistance of Mycobacterium tuberculosis to first and second line antitubercular drugs among specimens from a multispecialty hospital in Western Maharashtra. Settings and Design: This record-based study was conducted from January 2018. Records of sputum from 2013 to 2017 were obtained from patients with suspected TB. Subjects and Methods: Drug-sensitivity testing was performed by the mycobacterial growth indicator tube method. Sensitivity to first line and second line antitubercular drugs was tested. Statistical Analysis Used: Trend analysis and charts using MS Excel. Results: Among 734 patients, 701 (95.5%) were male and 33 (4.5%) were female. The analysis of our study result showed that 21.7% of patients were monodrug resistant. Out of 734 isolates, 56 (7.62%) showed multi- and 39 (5.6%) out of the 734 samples showed extensive drug-resistant TB. Conclusions: Our study confirms that drug resistance, including MDR, observed against all first-line TB drugs was a real threat in the management of TB infection. The resistance pattern in this study could assist the clinicians in providing appropriate treatment regimen to TB patients and improve their clinical outcome.

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.

Utility of Targeted, Amplicon-Based Deep Sequencing To Detect Resistance to First-Line Tuberculosis Drugs in Botswana.

Multidrug-resistant tuberculosis (TB) is an alarming threat, and targeted deep sequencing (DS) may be an effective method for rapid identification of drug-resistant profiles, including detection of heteroresistance. We evaluated the sensitivity and specificity of targeted DS versus phenotypic drug susceptibility testing (pDST) among patients starting first-line anti-TB therapy in Botswana. Overall, we found high concordance between DS and pDST. Lower sensitivity of DS, which targets established high-confidence resistance variants, was observed for detecting isoniazid resistance among HIV-infected patients.

First-line anti-tuberculosis drug resistance trends of Mycobacterium tuberculosis complex isolates. A tertiary hospital study in Turkey.

Tuberculosis (TB) is continuing to be a important public health problem in the undeveloped countries. Drug sensitivity rate should be monitored for the effective treatment and control in the TB. The aim of this study was to determine the rate of resistance to first line TB drugs in the Mycobacterium tuberculosis complex isolates. During one-year period, M. tuberculosis complex was isolated in the 1193 samples from 974 patients in the Mycobacterial Laboratory of Yedikule Chest Diseases and Chest Surgery Education and Research Hospital, Istanbul, Turkey. The majority of samples isolated in the M. tuberculosis complex were sputum (n= 897, 92.1%). Anti-TB drug susceptibility testing was performed with Mycobacterium Growth Indicator Tube 960 system. Two hundred and sixty isolat (26.7%) were resistant to at least one of the four first-line anti-TB drugs tested. One hundred ninety seven isolates were resistances to isoniazid (20.2%); 82 to rifampin (8.4%), 63 to ethambutol (6.5%) and 140 to streptomycin (14.4%). Of the 197 isoniazid-resistant isolates, 89 (45.2%) isolates was only isoniazid-resistance, only rifampin-resistance were found 15.9% (n= 13), ethambutol 7.9% (n= 5) and streptomycin 30.7% (n= 43). There were 48 (4.9%) isolates with two drugresistance, 22 (2.3%) isolates with three drug-resistance, and 42 (4.3%) isolates with four drug-resistance. The multidrug resistance rate was 7% (68 of 974). There was no relationship with between the frequency of TB drug resistance and gender or age. The isoniazid--resistance and streptomycin-resistance were seen to tend to increase if together considered the results of this study with outcomes of previously reported studies from Turkey in the 1998-2003, 2004-2007 and 2008-2010 years. Monitoring of drug susceptibility test results can contribute to the management of TB treatment and increase treatment success. Isoniazid-resistance and streptomycin-resistance tend to increase in Turkey. Further clinical studies are needed to investigate regional and global factors affecting the development of resistance to first-line TB drugs.

Safety of pyrazinamide-including regimen in late elderly patients with pulmonary tuberculosis: A prospective randomized open-label study

Pyrazinamide (PZA) -including regimen had not been fully recommended for late elderly patients with tuberculosis (TB) by Japanese Society for Tuberculosis until 2018. Studies on the safety of adding PZA to other first-line TB drugs for late elderly patients are limited. In this prospective randomized open-label study, we aimed to assess the safety of regimen including PZA for patients aged 80 or older.Patients in their eighties with smear-positive pulmonary TB without any liver diseases were randomly assigned to HRE (isoniazid, rifampicin, ethambutol) group or HREZ (HRE and PZA) group. The primary endpoint was discontinuation or interruption rate of treatment due to liver injury. Other endpoint included overall rate of liver injury, time to culture conversion, and overall mortality.Eighty-nine patients were assigned to either HRE group (n = 45) or HREZ group (n = 44). Clinical background was not different in two groups including age, smear grade, body weight, serum albumin, and activity degree. Discontinuation of treatment due to liver injury occurred in 15.6% of HRE group and 9.1% of HREZ group, which showed no statistical difference. Incidence of liver injury was also comparable between two groups. Overall mortality was statistically higher in HREZ group (3 in HRE vs. 10 in HREZ), although all deaths seemed to be irrelevant to PZA use. Time to culture conversion was significantly shorter in HREZ group (43.6 days vs. 30.2 days).In conclusion, regimen including PZA seems to be safe for late elderly patients with pulmonary TB.

First-line tuberculosis drug resistance patterns and associated risk factors in Germany, 2008-2017.

BackgroundDrug-resistant tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), poses a threat to public health. While standard surveillance focuses on Rifampicin and/or Isoniazid resistance, little is known about other resistance patterns. This study aims to identify predominant drug resistance (DR) patterns in Germany and risk factors associated with them in order to inform diagnostic and treatment strategies.MethodsCase-based TB surveillance data notified in Germany from 2008–2017 were utilized to investigate DR and MDR-TB patterns for Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E), and Streptomycin (S). Predominant patterns were further analyzed stratified by sex, age, country of birth, prior TB, and disease site. Multivariable logistic regression was conducted to determine risk factors associated with any resistance, MDR-TB, and complete HRZES resistance.Results26,228 cases with complete DST results were included in the study, among which 3,324 cases had any DR (12.7%). Four patterns were predominant, representing about ¾ of all cases with any resistance (S: 814 [3.1%]; H: 768 [2.9%]; HS: 552 [2.1%]; Z: 412 [1.6%]). High proportions of S and H resistances were found among both German and foreign-born populations, especially those born in Eastern Europe, and were unexpectedly high among children (H: 4.3%; S: 4.6%). Foreign-born cases had significantly higher proportion of any resistance (16.0%) and MDR-TB (3.3%) compared to German-born cases (8.3% and 0.6%). Of 556 MDR-TB cases, 39.2% showed complete HRZES resistance. Logistic regression revealed having prior TB and being foreign-born as consistently strong risk factors for any DR, MDR-TB, and complete HRZES resistance.ConclusionsDR patterns observed in Germany, particularly for MDR-TB were more complex than expected, highlighting the fact that detailed drug-testing results are crucial before incorporating HRZES drugs in MDR-TB treatment. Furthermore, the relatively high rate of H-resistance in Germany provides strong rationale against the use of only H-based preventive therapy for LTBI.

Optimal Sampling Strategies for Therapeutic Drug Monitoring of First-Line Tuberculosis Drugs in Patients with Tuberculosis.

BackgroundThe 24-h area under the concentration–time curve (AUC24)/minimal inhibitory concentration ratio is the best predictive pharmacokinetic/pharmacodynamic (PK/PD) parameter of the efficacy of first-line anti-tuberculosis (TB) drugs. An optimal sampling strategy (OSS) is useful for accurately estimating AUC24; however, OSS has not been developed in the fed state or in the early phase of treatment for first-line anti-TB drugs.MethodsAn OSS for the prediction of AUC24 of isoniazid, rifampicin, ethambutol and pyrazinamide was developed for TB patients starting treatment. A prospective, randomized, crossover trial was performed during the first 3 days of treatment in which first-line anti-TB drugs were administered either intravenously or in fasting or fed conditions. The PK data were used to develop OSS with best subset selection multiple linear regression. The OSS was internally validated using a jackknife analysis and externally validated with other patients from different ethnicities and in a steady state of treatment.ResultsOSS using time points of 2, 4 and 8 h post-dose performed best. Bias was < 5% and imprecision was < 15% for all drugs except ethambutol in the fed condition. External validation showed that OSS2-4-8 cannot be used for rifampicin in steady state conditions.ConclusionOSS at 2, 4 and 8 h post-dose enabled an accurate and precise prediction of AUC24 values of first-line anti-TB drugs in this population.Trial RegistrationClinicalTrials.gov (NCT02121314).

Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis.

We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin. Genotypes for SLCO1B1, NAT2, PXR, ABCB1and UGT1A genes were determined using a TaqMan® Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics. Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patients contributing drug concentrations, rapid and intermediate acetylators had 2.3- and 1.6-times faster isoniazid clearance than slow acetylators. No association was observed between rifampicin pharmacokinetics and SLCO1B1, ABCB1, UGT1Aor PXR genotypes. Clinical relevance of the effects of genetic variation on isoniazid concentrations and low first-line tuberculosis drug exposures observed require further investigation.