scholarly journals Population Pharmacokinetics of Cycloserine and Pharmacokinetic/Pharmacodynamic Target Attainment in Multidrug-Resistant Tuberculosis Patients Dosed with Terizidone

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Maxwell T. Chirehwa ◽  
Richard Court ◽  
Mariana de Kock ◽  
Lubbe Wiesner ◽  
Nihal de Vries ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Multidrug Resistant ◽  
Volume Of Distribution ◽  
Fat Free Mass ◽  
Development Of Resistance ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Group B ◽  
Disposition Model

ABSTRACT Cycloserine is a WHO group B drug for the treatment of multidrug-resistant tuberculosis (TB). Pharmacokinetic/pharmacodynamic data for cycloserine when dosed as terizidone are sparse. The aim of this analysis was to describe the population pharmacokinetics of cycloserine when administered as terizidone and predict the doses of terizidone attaining cycloserine exposures associated with efficacy. The plasma cycloserine level was measured 2 to 6 weeks after treatment initiation in patients hospitalized for second-line tuberculosis treatment. The pretreatment MICs of cycloserine were determined for the clinical isolates. We enrolled 132 participants with rifampicin-resistant TB; 79 were HIV positive. The median pretreatment MIC was 16 mg/liter. A one-compartment disposition model with two clearance pathways, nonrenal (0.35 liters/h) and renal (0.43 liters/h), described cycloserine pharmacokinetics well. Nonrenal clearance and the volume of distribution were allometrically scaled using fat-free mass. Smoking increased nonrenal clearance by 41%. Simulations showed that with daily doses of terizidone (750 mg and 1,000 mg for patients weighing ≤45 kg and >45 kg, respectively), the probability of maintaining the plasma cycloserine concentration above the MIC for more than 30% of the dosing interval (30% T>MIC) (which is associated with a 1.0-log10-CFU/ml kill in vitro) exceeded 90% at MIC values of ≤16 mg/liter, but the proportion of patients achieving 100% T>MIC (which is associated with the prevention of resistance) was more than 90% only at MICs of ≤8 mg/liter. Based on a target derived in vitro, the WHO-recommended doses of terizidone are effective for cycloserine MICs of ≤8 mg/liter, and higher doses are required to prevent the development of resistance.

The effect of isoniazid intake on ethionamide pharmacokinetics and target attainment in multidrug-resistant tuberculosis patients.

2021 ◽  
Author(s):  
Maxwell T. Chirehwa ◽  
Richard Court ◽  
Mariana de Kock ◽  
Lubbe Wiesner ◽  
Nihal de Vries ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Fat Free Mass ◽  
Hepatic Extraction ◽  
Target Attainment ◽  
Post Dose ◽  
Tuberculosis Patients ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Disposition Model

Ethionamide is recommended as part of regimens to treat multidrug-resistant and rifampicin-resistant tuberculosis. The study was conducted to (i) describe the distribution of ethionamide minimum inhibitory concentrations (MICs), (ii) describe the pharmacokinetics of ethionamide, and (iii) determine the probability of attaining target AUC 0-24 /MIC values associated with suppression of resistant subpopulation and microbial kill. Participants received 15–20 mg/kg of ethionamide daily (in 500 or 750 mg doses), as part of a multidrug regimen. Pretreatment MICs of ethionamide for M. tuberculosis sputum isolates were determined using Sensititre MYCOTB MIC plates. Plasma concentrations of ethionamide (measured pre-dose and at 2, 4, 6, 8 and 10 hours post-dose) were available for 84 patients. A one-compartment disposition model including a liver compartment capturing hepatic extraction, best described ethionamide pharmacokinetics. Clearance and volume were allometrically scaled using fat-free mass. Isoniazid co-administration reduced ethionamide clearance by 31% resulting in a 44% increase in AUC 0-24 . The median (range) MIC (n=111) was 2.5 mg/L (<0.3 to >40 mg/L). Simulations showed increased daily doses of ethionamide (1 250 mg, 1 500 mg, and 1 750 mg for patients weighing ≤45 kg, 46-70 kg, and >70 kg, respectively) resulted in the probability of attaining a f AUC 0-24 /MIC ratio ≥ 42 in more than 90% of patients, only at the lowest MIC of 0.3 mg/L. The WHO recommended doses of ethionamide do not achieve target concentrations even for the lowest MIC measured in the cohort.

scholarly journals Sulfamethoxazole Susceptibility of Mycobacterium tuberculosis Isolates from HIV-Infected Ugandan Adults with Tuberculosis Taking Trimethoprim-Sulfamethoxazole Prophylaxis

2015 ◽  
Vol 59 (9) ◽  
pp. 5844-5846 ◽  
Author(s):  
Sam Ogwang ◽  
Caryn E. Good ◽  
Brenda Okware ◽  
Mary Nsereko ◽  
Michael R. Jacobs ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Sub Saharan Africa ◽  
Content Type ◽  
Pulmonary Tb ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Sub Saharan

ABSTRACTAdditional drugs are needed for the treatment of multidrug-resistant tuberculosis (TB). Sulfamethoxazole has been shown to havein vitroactivity againstMycobacterium tuberculosis; however, there is concern about resistance given the widespread use of trimethoprim-sulfamethoxazole prophylaxis among HIV-infected patients in sub-Saharan Africa. Thirty-eight of 40Mycobacterium tuberculosisisolates (95%) from pretreatment sputum samples from Ugandan adults with pulmonary TB, including HIV-infected patients taking trimethoprim-sulfamethoxazole prophylaxis, were susceptible with MICs of ≤38.4 μg/ml.

scholarly journals RECHALLENGING TREATMENT PLAN FOR MULTIDRUG-RESISTANT TUBERCULOSIS IN DIABETIC PATIENT: A CASE REPORT

2019 ◽  
pp. 11-14 ◽  
Author(s):  
AHMED ALAA AL-TEMIMI ◽  
MUHAMMAD ZHARIF M NIZAM ◽  
YAHAYA HASSAN ◽  
NOORIZAN A AZIZ ◽  
MOHD FADLI MOHD ASMANI ◽  
...  
Keyword(s):  
Side Effect ◽  
Treatment Time ◽  
Treatment Plan ◽  
Multidrug Resistant ◽  
Prolonged Treatment ◽  
Development Of Resistance ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Hospital Acquired

Multidrug-resistant tuberculosis (MDR-TB) currently considers as the biggest issue and its subcategory, rifampicin-resistant TB (RR-TB). MDR-TB is defined as a resistant to isoniazid (H) and rifampicin (R), while the latter is resistant to rifampicin (R) only. Poorly controlled diabetes mellitus increases the risk of TB and leads to poor TB treatment outcomes as well it is consider potentially threating TB control. Difference in patients’ response and side effect developments toward anti-TB (ATB) medications requires rechallenging procedure that can be complicated at times. The management of MDR-TB can be complicated, especially, when the patient cannot tolerate the short regimen. Difference in patients’ response and side effect developments toward ATB medications requires rechallenging procedure which can have prolonged treatment time, hospital stay, and make patients exposed to hospital-acquired infection. This challenges and obstacles, however, could be prevented earlier by having strong DOTS strategy to prevent the development of resistance and reactivation of TB.

scholarly journals Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4457-4463 ◽  
Author(s):  
Benoit Lechartier ◽  
Stewart T. Cole
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Drug Resistant Strains ◽  
Transfer Chain

ABSTRACTClofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. InMycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O2. CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM againstM. tuberculosisand found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergisticin vitrowith benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was testedin vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains ofM. tuberculosis.

scholarly journals Synthesis, Characterization and Antituberculosis Activity of Biologically Nanostructured Zinc and Titanium Metal Compounds

2020 ◽  
Vol 32 (6) ◽  
pp. 1286-1290
Author(s):  
Savita Belwal ◽  
Sujana Kariveda ◽  
Saritha Ramagiri
Keyword(s):  
Multidrug Resistant ◽  
Metal Compounds ◽  
Zinc Compounds ◽  
Macrotyloma Uniflorum ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Transmission Electron ◽  
H37rv Strain ◽  
Mdr Tb

Green chemistry was used to obtain nano-range sized titanium and zinc compounds from their macro-sizes by using an aqueous extract of horse gram (Macrotyloma uniflorum). Ultraviolet-visible (UV-vis) and Fourier-transform infrared (FTIR) spectrophotometers were employed for characterizing the nanoparticles of biosynthesized metal nanoparticles. Transmission electron microscopy (TEM) was used to analyse the reduced nanoparticles of Ti and Zn metals. Microdilution was employed to determine in vitro properties, such as effects of nanocomplex antimicrobials on Mycobacterium tuberculosis (MTB) H37RV strain. MTB strains isolated from patients with multidrug-resistant tuberculosis (MDR-TB) were resistant to first-line drugs. Novel synthesized nano-complexes exhibited potential antituberculosis activities. Titanium nanocomplexes exhibited the highest minimal inhibitory concentration (MIC) in comparison to zinc nanocomplex. In a cytotoxic study, an IC50 of 1000 μg/mL, for both Ti and Zn nanocomplexes, was reported, and thus, these complexes were non-toxic when compared to isoniazid.

scholarly journals Neuropsychiatric reactions induced by cycloserine in the treatment of multidrug-resistant tuberculosis: what an Indian female patient tells us

2019 ◽  
Vol 12 (12) ◽  
pp. e230993 ◽  
Author(s):  
Enrica Intini ◽  
Girija Kishore ◽  
Luca Richeldi ◽  
Zarir F Udwadia
Keyword(s):  
Adverse Events ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Health Crisis ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Multi Drug Resistant Tuberculosis ◽  
Group B

Multidrug-resistant tuberculosis continues to be a public health crisis. Urgent action is required to improve the coverage and quality of diagnosis, treatment and care for people affected by drug-resistant tuberculosis. To implement tuberculosis control, in 2018, WHO recommended cycloserine as one of the Group B drugs. Following this recommendation, cycloserine should be generally included in the starting line-up in the longer regimen for the treatment of multidrug-resistant tuberculosis. However, neurological toxicity associated with this drug concerns clinicians and limits its use. In this paper, we present a case of a 48-year-old woman with a diagnosis of multidrug-resistant tuberculosis treated with cycloserine, who developed psychiatric adverse events after 3 months of administration. This case shows the need for close psychiatric follow-up to promptly detect adverse events in patients receiving regimens for multi-drug resistant tuberculosis.

Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis

2021 ◽  
Author(s):  
Tomohiro Sasaki ◽  
Elin M. Svensson ◽  
Xiaofeng Wang ◽  
Yanlin Wang ◽  
Jeffrey Hafkin ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Population Pharmacokinetic Analysis ◽  
Apparent Volume ◽  
Multidrug Resistant ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 to 17 years old, enrolled in 2 clinical trials, were utilized for the analysis. The final dataset contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two compartment models for each component with linear elimination were selected to characterize the disposition of delamanid and DM-6705, respectively. The covariates included in the model were body weight on apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible vs film coated tablet) on mean absorption time; age, formulation, and dose on bioavailability of delamanid; age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB, QT corrected by Bazett’s' formula) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc value were less than 10 ms at the simulated Cmax of DM-6705 following administration of maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive delamanid.

scholarly journals Population Pharmacokinetics and Pharmacodynamics of Ofloxacin in South African Patients with Multidrug-Resistant Tuberculosis

2012 ◽  
Vol 56 (7) ◽  
pp. 3857-3863 ◽  
Author(s):  
Emmanuel Chigutsa ◽  
Sandra Meredith ◽  
Lubbe Wiesner ◽  
Nesri Padayatchi ◽  
Joe Harding ◽  
...  
Keyword(s):  
South Africa ◽  
Population Pharmacokinetics ◽  
South African ◽  
Multidrug Resistant ◽  
Pharmacokinetic Data ◽  
Target Attainment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Study Population ◽  
African Patients

ABSTRACTDespite the important role of fluoroquinolones and the predominant use of ofloxacin for treating multidrug-resistant tuberculosis in South Africa, there are limited data on ofloxacin pharmacokinetics in patients with multidrug-resistant tuberculosis, no ofloxacin pharmacokinetic data from South African patients, and no direct assessment of the relationship between ofloxacin pharmacokinetics and the MIC of ofloxacin of patient isolates. Our objectives are to describe ofloxacin pharmacokinetics in South African patients being treated for multidrug-resistant tuberculosis and assess the adequacy of ofloxacin drug exposure with respect to the probability of pharmacodynamic target attainment (area under the time curve/MIC ratio of at least 100). Sixty-five patients with multidrug-resistant tuberculosis were recruited from 2 hospitals in South Africa. We determined the ofloxacin MICs for theMycobacterium tuberculosisisolates from baseline sputum specimens. Patients received daily doses of 800 mg ofloxacin, in addition to other antitubercular drugs. Patients underwent pharmacokinetic sampling at steady state. NONMEM was used for data analysis. The population pharmacokinetics of ofloxacin in this study has been adequately described. The probability of target attainment expectation in the study population was 0.45. Doubling the dose to 1,600 mg could increase this to only 0.77. The currently recommended ofloxacin dose appeared inadequate for the majority of this study population. Studies to assess the tolerability of higher doses are warranted. Alternatively, ofloxacin should be replaced with more potent fluoroquinolones.

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