Population Pharmacokinetics of Oral Levofloxacin in Healthy Volunteers and Dosing Optimization for Multidrug‐resistant Tuberculosis Therapy

2021 ◽  
Author(s):  
Apinya Boonpeng ◽  
Sutep Jaruratanasirikul ◽  
Thitima Wattanavijitkul ◽  
Monchana Nawakitrangsan ◽  
Maseetoh Samaeng
Keyword(s):  
Healthy Volunteers ◽  
Population Pharmacokinetics ◽  
Multidrug Resistant ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Tuberculosis Therapy ◽  
Dosing Optimization

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.

scholarly journals Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis

2006 ◽  
Vol 50 (8) ◽  
pp. 2621-2625 ◽  
Author(s):  
Eric Nuermberger ◽  
Ian Rosenthal ◽  
Sandeep Tyagi ◽  
Kathy N. Williams ◽  
Deepak Almeida ◽  
...  
Keyword(s):  
Murine Model ◽  
Multidrug Resistant ◽  
First Line ◽  
Duration Of Treatment ◽  
Standard Regimen ◽  
Drug Candidates ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Lower Lung ◽  
Tuberculosis Therapy

ABSTRACT The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.

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.

scholarly journals Lack of Activity of Orally Administered Clofazimine against Intracellular Mycobacterium tuberculosis in Whole-Blood Culture

2004 ◽  
Vol 48 (8) ◽  
pp. 3133-3135 ◽  
Author(s):  
Ernestas Janulionis ◽  
Carolina Sofer ◽  
Ho-Yeon Song ◽  
Robert S. Wallis
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Blood Culture ◽  
Healthy Volunteers ◽  
Total Dose ◽  
Whole Blood ◽  
Active Drug ◽  
Multidrug Resistant ◽  
Blood Cultures ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

ABSTRACT The activity of oral clofazimine against intracellular Mycobacterium tuberculosis was compared to that of ofloxacin in healthy volunteers by the use of whole-blood cultures. Clofazimine was inactive whether it was tested alone or combined with other drugs that are used to treat multidrug-resistant tuberculosis, despite a total dose of 2 g. Kanamycin was the most active drug tested.

scholarly journals High frequency of azole resistant Candida spp. colonization among presumptive multidrug resistant tuberculosis (MDR-TB) patients

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242542
Author(s):  
Surya Darma ◽  
Angga Ambara ◽  
Abu Tholib Aman ◽  
Luthvia Annisa ◽  
Nurrokhman ◽  
...  
Keyword(s):  
Candida Albicans ◽  
High Frequency ◽  
Antifungal Susceptibility ◽  
Multidrug Resistant ◽  
Dependent Manner ◽  
Candida Spp ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Tuberculosis Therapy

Background Tuberculosis is one of the major causes of death globally. The problems become even more complicated with the rise in prevalence of multidrug resistant tuberculosis (MDR-TB). Many diseases have been reported to occur with tuberculosis making it more difficult to manage. Candida spp., which are yeast-like fungi and a constituent of normal flora in humans, are notoriously reported to be one of the most common opportunistic nosocomial infections. This study aimed to measure the proportion of presumptive MDR-TB patients colonized with Candida spp. and to characterize its susceptibility against azole group antifungal agents. Methods Sputum from presumptive MDR-TB patients were collected and examined for the presence of Mycobacterium tuberculosis and its rifampicin resistant status using GeneXpert. It was further cultured on Sabouroud’s Dextrose Agar (SDA) to isolate the Candida spp. The Candida species were determined using HiCrome™ Candidal Differential Agar. Antifungal susceptibility was tested using microbroth dilution methods. Checkerboard microdilution assays were performed to measure the interaction between rifampicin and fluconazole to C. albicans. Results There were 355 presumptive MDR-TB patients enrolled. A total of 101 (28.4%) patients were confirmed to have M. tuberculosis. There were 113 (31.8%) sputum positive for Candida spp., which corresponded to 149 Candida spp. isolates. Candida albicans was the most frequent (53.7%) species isolated from all patients. The susceptibility of Candida spp. against fluconazole, itraconazole, and ketoconazole were 38.3%, 1.3%, and 10.7% respectively. There was significant association between rifampicin exposure history and susceptibility of Candida albicans against fluconazole (Odds Ratio: 9.96; 95% CI: 1.83–54.19; p <0.01), but not for ketoconazole and itraconazole. The checkerboard microdilution assays showed that rifampicin decreased the fungicidal activity of fluconazole to C. albicans in a dose-dependent manner. Conclusion There was high frequency of azole resistant Candida spp. isolates colonizing the respiratory tract of presumptive MDR-TB patients. This presence might indicate the association of chronic exposure to rifampicin, the main drug for tuberculosis therapy, with the induction of azole resistance.

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