scholarly journals Pharmacokinetics of ertapenem in patients with multidrug-resistant tuberculosis

2016 ◽  
Vol 47 (4) ◽  
pp. 1229-1234 ◽  
Author(s):  
Sander P. van Rijn ◽  
Richard van Altena ◽  
Onno W. Akkerman ◽  
Dick van Soolingen ◽  
Tridia van der Laan ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Medical Center ◽  
Multidrug Resistant ◽  
Sputum Smear ◽  
Antimicrobial Drugs ◽  
Time Curve ◽  
Resistant Tuberculosis ◽  
Pharmacodynamic Profile ◽  
Mdr Tb ◽  
The Mean

Treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is becoming more challenging because of increased levels of drug resistance against second-line TB drugs. One promising group of antimicrobial drugs is carbapenems. Ertapenem is an attractive carbapenem for the treatment of MDR- and XDR-TB because its relatively long half-life enables once-daily dosing.A retrospective study was performed for all patients with suspected MDR-TB at the Tuberculosis Center Beatrixoord of the University Medical Center Groningen (Haren, the Netherlands) who received ertapenem as part of their treatment regimen between December 1, 2010 and March 1, 2013. Safety and pharmacokinetics were evaluated.18 patients were treated with 1000 mg ertapenem for a mean (range) of 77 (5–210) days. Sputum smear and culture were converted in all patients. Drug exposure was evaluated in 12 patients. The mean (range) area under the concentration–time curve up to 24 h was 544.9 (309–1130) h·mg·L−1. The mean (range) maximum observed plasma concentration was 127.5 (73.9–277.9) mg·L−1.In general, ertapenem treatment was well tolerated during MDR-TB treatment and showed a favourable pharmacokinetic/pharmacodynamic profile in MDR-TB patients. We conclude that ertapenem is a highly promising drug for the treatment of MDR-TB that warrants further investigation.

scholarly journals Outcomes of Community-Based Systematic Screening of Household Contacts of Patients with Multidrug-Resistant Tuberculosis in Myanmar

2019 ◽  
Vol 5 (1) ◽  
pp. 2
Author(s):  
Nang Thu Thu Kyaw ◽  
Aung Sithu ◽  
Srinath Satyanarayana ◽  
Ajay M. V. Kumar ◽  
Saw Thein ◽  
...  
Keyword(s):  
Chest Radiography ◽  
Multidrug Resistant ◽  
Sputum Smear ◽  
Community Based ◽  
Household Contacts ◽  
Resistant Tuberculosis ◽  
Symptom Screening ◽  
Multidrug Resistant Tuberculosis ◽  
Screening Algorithm ◽  
Mdr Tb

Screening of household contacts of patients with multidrug-resistant tuberculosis (MDR-TB) is a crucial active TB case-finding intervention. Before 2016, this intervention had not been implemented in Myanmar, a country with a high MDR-TB burden. In 2016, a community-based screening of household contacts of MDR-TB patients using a systematic TB-screening algorithm (symptom screening and chest radiography followed by sputum smear microscopy and Xpert-MTB/RIF assays) was implemented in 33 townships in Myanmar. We assessed the implementation of this intervention, how well the screening algorithm was followed, and the yield of active TB. Data collected between April 2016 and March 2017 were analyzed using logistic and log-binomial regression. Of 620 household contacts of 210 MDR-TB patients enrolled for screening, 620 (100%) underwent TB symptom screening and 505 (81%) underwent chest radiography. Of 240 (39%) symptomatic household contacts, 71 (30%) were not further screened according to the algorithm. Children aged <15 years were less likely to follow the algorithm. Twenty-four contacts were diagnosed with active TB, including two rifampicin- resistant cases (yield of active TB = 3.9%, 95% CI: 2.3%–6.5%). The highest yield was found among children aged <5 years (10.0%, 95% CI: 3.6%–24.7%). Household contact screening should be strengthened, continued, and scaled up for all MDR-TB patients in Myanmar.

scholarly journals Pharmacokinetics of Second-Line Antituberculosis Drugs in Children with Multidrug-Resistant Tuberculosis in India

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Agibothu Kupparam Hemanth Kumar ◽  
Alok Kumar ◽  
Thiruvengadam Kannan ◽  
Rakesh Bhatia ◽  
Dipti Agarwal ◽  
...  
Keyword(s):  
High Performance ◽  
Linear Regression Analysis ◽  
Multidrug Resistant ◽  
Control Programme ◽  
Second Line ◽  
Time Curve ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
The Government

ABSTRACTWe studied the pharmacokinetics of levofloxacin (LFX), pyrazinamide (PZA), ethionamide (ETH), and cycloserine (CS) in children with multidrug-resistant tuberculosis (MDR-TB) who were being treated according to the Revised National TB Control Programme (RNTCP) guidelines in India. This observational, pharmacokinetic study was conducted in 25 children with MDR-TB at the Sarojini Naidu Medical College, Agra, India, who were being treated with a 24-month daily regimen. Serial blood samples were collected after directly observed administration of drugs. Estimations of plasma LFX, PZA, ETH, and CS were undertaken according to validated methods by high-performance liquid chromatography. Adverse events were noted at 6 months of treatment. The peak concentration (Cmax) of LFX was significantly higher in female than male children (11.5 μg/ml versus 7.3 μg/ml;P= 0.017). Children below 12 years of age had significantly higher ETH exposure (area under the concentration-time curve from 0 to 8 h [AUC0–8]) than those above 12 years of age (17.5 μg/ml · h versus 9.4 μg/ml;P= 0.030). Multiple linear regression analysis showed significant influence of gender onCmaxof ETH and age onCmaxand AUC0–8of CS. This is the first and only study from India reporting on the pharmacokinetics of LFX, ETH, PZA, and CS in children with MDR-TB treated in the Government of India program. More studies on the safety and pharmacokinetics of second-line anti-TB drugs in children with MDR-TB from different settings are required.

scholarly journals Prevalence and Factors Associated with Multidrug-Resistant Tuberculosis (MDR-TB) among Presumptive MDR-TB Patients in Tigray Region, Northern Ethiopia

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Kibriti Mehari ◽  
Tsehaye Asmelash ◽  
Haftamu Hailekiros ◽  
Tewolde Wubayehu ◽  
Hagos Godefay ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Multidrug Resistant ◽  
Sputum Smear ◽  
Northern Ethiopia ◽  
Crude Odds Ratio ◽  
Factors Associated ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Regional State ◽  
Mdr Tb

Background. Tuberculosis (TB) is one of the major public health problems. There are alarming reports of increasing multidrug-resistant tuberculosis (MTR-TB) from various parts of the globe, including Ethiopia. This study was designed to determine the prevalence and factors associated with MDR-TB among presumptive MDR-TB cases in Tigray Regional State, Ethiopia. Methods. A cross-sectional study was conducted in Tigray Regional State from 2015 to 2016. Two hundred sputum samples were collected, transported, processed using 2% N-acetyl-L-cysteine-sodium hydroxide, and cultured in LJ medium. Besides, the microscopic examination was performed after ZN staining. Moreover, drug susceptibility test was done using molecular line probe assay. Descriptive statistics and binary and multivariable logistic regression were done. A statistical test was regarded as significant when the P value was <0.05. Results. The prevalence of MDR-TB was found to be 18.5%. About one-fourth (26.5%) of the study participants had sputum smear positive for acid-fast bacilli (AFB). TB culture was positive in 37% of the samples, and rifampicin mono-resistant cases accounted for 3.5% of the presumptive MDR-TB cases. Three (1.5%) were new MDR-TB cases, while the rest had been treated previously for TB. Most (63.5%) of the MDR-TB cases were from 15 to 44 years of age. Age was associated with MDR-TB with a crude odds ratio of 1.06 (CI: 1.02–1.10) and adjusted odds ratio of 1.06 (CI: 1.00–1.11). Conclusions. The prevalence of MDR-TB was found to be high. Preventive measures should be taken to prevent the transmission of MDR-TB in the community.

scholarly journals Cumulative Fraction of Response for Once- and Twice-Daily Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01207-20 ◽  
Author(s):  
Suresh Mallikaarjun ◽  
Moti L. Chapagain ◽  
Tomohiro Sasaki ◽  
Norimitsu Hariguchi ◽  
Devyani Deshpande ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
System Model ◽  
Qtc Interval ◽  
Fiber System ◽  
Time Curve ◽  
Once Daily ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Concentration Time ◽  
Mdr Tb

ABSTRACTPharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC0–24/MIC), with a PDT of 252. Second, in the hollow-fiber system model of tuberculosis, plasma-equivalent PDTs were identified as an AUC0–24/MIC of 195 in log-phase bacteria and 201 in pH 5.8 cultures. Third, delamanid plasma AUC0–24/MIC and sputum bacterial decline data from two early bactericidal activity trials identified a clinical PDT of AUC0–24/MIC of 171. Finally, the CFRs for the currently approved 100-mg BID dose were determined to be above 95% in two MDR-TB clinical trials. The CFR for the 200-mg QD dose, evaluated in a trial in which delamanid was administered as 100 mg BID for 8 weeks plus 200 mg QD for 18 weeks, was 89.3% based on the mouse PDT and >90% on the other PDTs. QTcF (QTc interval corrected for heart rate by Fridericia’s formula) prolongation was approximately 50% lower for the 200 mg QD dose than the 100 mg BID dose. In conclusion, while CFRs of 100 mg BID and 200 mg QD delamanid were close to or above 90% in patients with MDR-TB, more-convenient once-daily dosing of delamanid is feasible and likely to have less effect on QTcF prolongation.

scholarly journals Effect of tablet crushing on drug exposure in the treatment of multidrug-resistant tuberculosis

2019 ◽  
Vol 23 (10) ◽  
pp. 1068-1074 ◽  
Author(s):  
R. Court ◽  
M. T. Chirehwa ◽  
L. Wiesner ◽  
N. de Vries ◽  
J. Harding ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Geometric Mean ◽  
Area Under The Curve ◽  
Compartmental Analysis ◽  
Multidrug Resistant ◽  
Geometric Mean Ratio ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

SETTING: Treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) are poor. Due to drug toxicity and a long treatment duration, approximately half of patients are treated successfully. Medication is often crushed for patients who have difficulty swallowing whole tablets. Whether crushing tablets affects drug exposure in MDR-TB treatment is not known.OBJECTIVE AND DESIGN: We performed a sequential pharmacokinetic study in patients aged >18 years on MDR-TB treatment at two hospitals in Cape Town, South Africa. We compared the bioavailability of pyrazinamide, moxifloxacin, isoniazid (INH), ethambutol and terizidone when the tablets were crushed and mixed with water before administration vs. swallowed whole. We sampled blood at six time points over 10 h under each condition separated by 2 weeks. Non-compartmental analysis was used to derive the key pharmacokinetic measurements.RESULTS: Twenty participants completed the study: 15 were men, and the median age was 31.5 years. There was a 42% reduction in the area under the curve AUC0–10 of INH when the tablets were crushed compared with whole tablets (geometric mean ratio 58%; 90%CI 47–73). Crushing tablets of pyrazinamide, moxifloxacin, ethambutol and terizidone did not affect the bioavailability significantly.CONCLUSION: We recommend that crushing of INH tablets in the MDR-TB treatment regimen be avoided. Paediatric INH formulations may be a viable alternative if the crushing of INH tablets is indicated.

scholarly journals Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Linezolid in Patients with Multidrug-Resistant Tuberculosis

2012 ◽  
Vol 56 (11) ◽  
pp. 5758-5763 ◽  
Author(s):  
D. H. Vu ◽  
M. S. Bolhuis ◽  
R. A. Koster ◽  
B. Greijdanus ◽  
W. C. M. de Lange ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Multidrug Resistant ◽  
Dried Blood Spot ◽  
Therapeutic Drug ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Blood Spot

ABSTRACTLinezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring might be hindered in many parts of the world by logistical problems that may be solved by dried blood spot (DBS) sampling. The aim of this study was to develop and validate a novel method for TDM of linezolid in MDR-TB patients using DBS sampling. Plasma, venous DBS, and capillary DBS specimens were obtained simultaneously from eight patients receiving linezolid. A DBS sampling method was developed and clinically validated by comparing DBS with plasma results using Passing-Bablok regression and Bland-Altman analysis. This study showed that DBS analysis was reproducible and robust. Accuracy and between- and within-day precision values from three validations presented as bias and coefficient of variation (CV) were less than 17.2% for the lower limit of quantification and less than 7.8% for other levels. The method showed a high recovery of approximately 95% and a low matrix effect of less than 8.7%. DBS specimens were stable at 37°C for 2 months and at 50°C for 1 week. The ratio of the concentration of linezolid in DBS samples to that in plasma was 1.2 (95% confidence interval [CI], 1.12 to 1.27). Linezolid exposure calculated from concentrations DBS samples and plasma showed good agreement. In conclusion, DBS analysis of linezolid is a promising tool to optimize linezolid treatment in MDR-TB patients. An easy sampling procedure and high sample stability may facilitate TDM, even in underdeveloped countries with limited resources and where conventional plasma sampling is not feasible.

scholarly journals Pharmacokinetics and Safety of Ofloxacin in Children with Drug-Resistant Tuberculosis

2015 ◽  
Vol 59 (10) ◽  
pp. 6073-6079 ◽  
Author(s):  
Anthony J. Garcia-Prats ◽  
Heather R. Draper ◽  
Stephanie Thee ◽  
Kelly E. Dooley ◽  
Helen M. McIlleron ◽  
...  
Keyword(s):  
Body Weight ◽  
Multivariable Analysis ◽  
Multidrug Resistant ◽  
Preventive Therapy ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Treatment Regimens ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Mdr Tb

ABSTRACTOfloxacin is widely used for the treatment of multidrug-resistant tuberculosis (MDR-TB). Data on its pharmacokinetics and safety in children are limited. It is not known whether the current internationally recommended pediatric dosage of 15 to 20 mg/kg of body weight achieves exposures reached in adults with tuberculosis after a standard 800-mg dose (adult median area under the concentration-time curve from 0 to 24 h [AUC0–24], 103 μg · h/ml). We assessed the pharmacokinetics and safety of ofloxacin in children <15 years old routinely receiving ofloxacin for MDR-TB treatment or preventive therapy. Plasma samples were collected predose and at 1, 2, 4, 8, and either 6 or 11 h after a 20-mg/kg dose. Pharmacokinetic parameters were calculated using noncompartmental analysis. Children with MDR-TB disease underwent long-term safety monitoring. Of 85 children (median age, 3.4 years), 11 (13%) were HIV infected, and of 79 children with evaluable data, 14 (18%) were underweight. The ofloxacin mean (range) maximum concentration (Cmax), AUC0–8, and half-life were 8.97 μg/ml (2.47 to 14.4), 44.2 μg · h/ml (12.1 to 75.8), and 3.49 h (1.89 to 6.95), respectively. The mean AUC0–24, estimated in 72 participants, was 66.7 μg · h/ml (range, 18.8 to 120.7). In multivariable analysis, AUC0–24was increased by 1.46 μg · h/ml for each 1-kg increase in body weight (95% confidence interval [CI], 0.44 to 2.47;P= 0.006); no other assessed variable contributed to the model. No grade 3 or 4 events at least possibly attributed to ofloxacin were observed. Ofloxacin was safe and well tolerated in children with MDR-TB, but exposures were well below reported adult values, suggesting that dosage modification may be required to optimize MDR-TB treatment regimens in children.

scholarly journals Risk factors for multiple drug resistant tuberculosis relapses

2020 ◽  
Vol 98 (11) ◽  
pp. 21-26
Author(s):  
А. S. Аlliluev ◽  
O. V. Filinyuk ◽  
E. E. Shnayder ◽  
P. N. Golubchikov ◽  
D. E. Аmichba
Keyword(s):  
Risk Factors ◽  
Medical Center ◽  
Multiple Drug ◽  
Sputum Smear ◽  
Smear Microscopy ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Multiple Drug Resistant ◽  
Mdr Tb

The objective of the study: to identify risk factors for relapses in patients after the effective course of chemotherapy for multiple drug resistant tuberculosis (MDR TB). Subjects and methods. Medical files of 346 adult MDR TB patients were analyzed, they all had the effective treatment as per regimen IV in Tomsk Phthisiopulmonology Medical Center in 2009-2011. They were divided into 2 groups: Group 1 included 35 patients who developed a relapse of tuberculosis over the next 5 years; Group 2 consisted of 311 patients who had no relapse of the disease over the next 5 years. Results. The relapse rate in effectively treated MDR TB patients made 10.1% (35/346 patients). The following social factors contributed to higher chances of the relapse: retirement age (p = 0.045; OR = 2.86 [1.14-7.20]) and disability due to somatic diseases (p < 0.001; OR = 4.82 [2.13-10.90]); while biomedical factors were the following: HIV infection (OR = 19.19 [5.29-69.56]), mental illness (OR = 5.85 [2.27-15.03]), tobacco smoking (OR = 3.16 [1.08-9.20]). People with history of tuberculosis relapses (OR = 12.17 [4.19-35.34]) have higher chances of relapse, as well as those having the following characteristics of the tuberculosis disease during the effective chemotherapy course: destruction of lung tissue (OR = 7.48 [1.76-31.80]), positive results of sputum smear microscopy (OR = 2.91 [1.28-6.61]), persisting bacterial excretion (by culture) after 2 months of chemotherapy (OR = 4.98 [2.41-10.29]).

scholarly journals Comparative Utility of Genetic Determinants of Drug Resistance and Phenotypic Drug Susceptibility Profiling in Predicting Clinical Outcomes in Patients With Multidrug-Resistant Mycobacterium tuberculosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Yang Che ◽  
Tianchi Yang ◽  
Lv Lin ◽  
Yue Xiao ◽  
Feng Jiang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Latent Class ◽  
Treatment Success ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Sputum Smear ◽  
Genetic Determinants ◽  
Resistant Tuberculosis ◽  
Mdr Tb

Setting: Programmatic management of drug-resistant tuberculosis in Ningbo, China.Objective: To assess whether data-driven genetic determinants of drug resistance patterns could outperform phenotypic drug susceptibility testing in predicting clinical meaningful outcomes among patients with multidrug-resistant tuberculosis (MDR-TB).Design: We conducted a prospective cohort study of 104 MDR-TB patients. All MDR-TB isolates underwent drug susceptibility testing and genotyping for mutations that could cause drug resistance. Study outcomes were time to sputum smear conversion and probability of treatment success, as well as time to culture conversion within 6 months. Data were analyzed using latent class analysis, Kaplan–Meier curves, and Cox regression models.Results: We report that latent class analysis of data identified two latent classes that predicted sputum smear conversion with P = 0.001 and area under receiver-operating characteristic curve of 0.73. The predicted latent class memberships were associated with superior capability in predicting sputum culture conversion at 6 months and overall treatment success compared to phenotypic drug susceptibility profiling using boosted logistic regression models.Conclusion: These results suggest that genetic determinants of drug resistance in combination with phenotypic drug-resistant tests could serve as useful biomarkers in predicting treatment prognosis in MDR-TB.

scholarly journals Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Jansy Sarathy ◽  
Landry Blanc ◽  
Nadine Alvarez-Cabrera ◽  
Paul O’Brien ◽  
Isabela Dias-Freedman ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Rabbit Model ◽  
Drug Efficacy ◽  
Multidrug Resistant ◽  
Lung Lesion ◽  
Time Curve ◽  
Bacterial Populations ◽  
Resistant Tuberculosis ◽  
Mdr Tb ◽  
Drug Regimens

ABSTRACTFluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of “universal” drug regimens, aiming to treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacies in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than the plasma concentrations and potency measured in standard growth inhibition assays and are better suited to determinations of whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. On the basis of these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (the ranges of the plasma AUC/MIC ratio [i.e., the area under the concentration-time curve over 24 h in the steady state divided by the MIC] are 46 to 86 for moxifloxacin and 74 to 258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level and in sterilizing cellular and necrotic lesions. Collectively, these results show that PK/PD data obtained at the site of infection represent an adequate predictor of drug efficacy against TB and constitute the baseline required to explore synergies, antagonism, and drug-drug interactions in fluoroquinolone-containing regimens.

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