Linezolid: a Promising Agent for the Treatment&amp;nbsp;of Multiple and Extensively Drug-Resistant&amp;nbsp;Tuberculosis

Fermeli, Dionysia; Marantos, Theodoros; Liarakos, Alexandros Leonidas; Panayiotakopoulos, George; Dedes, Vasileios; Panoutsopoulos, Georgios I.

doi:10.3897/folmed.62.e48742

Cited by 4 publications

(3 citation statements)

References 97 publications

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“…Linezolid, the prototype member of the oxazolidinone antimicrobial class, has potent in vitro antituberculosis activity and is associated with improved treatment outcomes when added to multidrug regimens for DR-TB (5,6). The World Health Organization recommends linezolid at a dose of 600 mg daily for most patients with RR-TB.…”

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confidence: 99%

Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis

Abdelwahab

Wasserman

Brust

et al. 2021

Antimicrob Agents Chemother

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BACKGROUND Linezolid is widely used for drug-resistant tuberculosis (DR-TB) but has a narrow therapeutic index. To inform dose optimisation, we aimed to characterise the population pharmacokinetics of linezolid in South African participants with DR-TB and explore the effect of covariates, including HIV-co-infection, on drug exposure. METHODS Data were obtained from pharmacokinetic sub-studies in a randomised controlled trial and an observational cohort study, both of which enrolled adults with drug-resistant pulmonary tuberculosis. Participants underwent intensive and sparse plasma sampling. We analyzed linezolid concentration data using non-linear mixed-effects modelling and performed simulations to estimate attainment of putative efficacy and toxicity targets. RESULTS 124 participants provided 444 plasma samples; 116 were on the standard daily dose of 600 mg, while 19 had dose reduction to 300 mg due to adverse events. Sixty-one participants were female, 71 were HIV-positive, and median weight was 56 kg (IQR 50 - 63). In the final model, typical values for clearance and central volume were 3.57 L/h and 40.2 L, respectively. HIV co-infection had no significant effect on linezolid exposure. Simulations showed that 600 mg dosing achieved the efficacy target ( f AUC 0-24h /MIC > 119 at MIC level of 0.5 mg/L) with 96% probability but had 56% probability of exceeding safety target ( trough 24h > 2 mg/L ). The 300 mg dose did not achieve adequate efficacy exposures. CONCLUSION Our model characterised population pharmacokinetics of linezolid in South African patients with DR-TB and supports the 600 mg daily dose with safety monitoring.

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confidence: 99%

Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis

Abdelwahab

Wasserman

Brust

et al. 2021

Antimicrob Agents Chemother

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“…Linezolid (LZD) is an oxazolidinone drug with antimicrobial activity by the inhibition of protein synthesis, particularly binding to rRNA 23S from ribosomal subunit 50S. LZD inhibits the formation of the ribosomal complex 70S, leading to a non-functional initiation complex, and, consequently, decreasing the efficiency of the translation process (Hashemian et al, 2018;Fermeli et al, 2020). Structurally, LZD is formed by an N-aryl ring core, which is important to its function as an antimicrobial.…”

Section: Resistance To Other Drugsmentioning

confidence: 99%

Mutations and insights into the molecular mechanisms of resistance of Mycobacterium tuberculosis to first-line

Rossini

Dias

2023

Genet. Mol. Biol.

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Genetically antimicrobial resistance in Mycobacterium tuberculosis is currently one of the most important aspects of tuberculosis, considering that there are emerging resistant strains for almost every known drug used for its treatment. There are multiple antimicrobials used for tuberculosis treatment, and the most effective ones are the first-line drugs, which include isoniazid, pyrazinamide, rifampicin, and ethambutol. In this context, understanding the mechanisms of action and resistance of these molecules is essential for proposing new therapies and strategies of treatment. Additionally, understanding how and where mutations arise conferring a resistance profile to the bacteria and their effect on bacterial metabolism is an important requisite to be taken in producing safer and less susceptible drugs to the emergence of resistance. In this review, we summarize the most recent literature regarding novel mutations reported between 2017 and 2022 and the advances in the molecular mechanisms of action and resistance against first-line drugs used in tuberculosis treatment, highlighting recent findings in pyrazinamide resistance involving PanD and, additionally, resistance-conferring mutations for novel drugs such as bedaquiline, pretomanid, delamanid and linezolid.

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“…Linezolid belongs to the oxazolidone class of antimicrobial agents that inhibits protein synthesis b interacting with the 70s bacterial ribosomes [ 188 ]. It has been shown to improve the treatment outcome of patients with drug-resistant TB [ 189 , 190 ]. The WHO has approved the usage of linezolid (600 mg) daily for rifampicin-resistant TB.…”

Section: Current Approaches For the Treatment Of Drug-resistant Tbmentioning

confidence: 99%

Tools to Alleviate the Drug Resistance in Mycobacterium tuberculosis

et al. 2022

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Mycobacterium tuberculosis (Mtb), an acid-fast bacillus that causes Tuberculosis (TB), is a pathogen that caused 1.5 million deaths in 2020. As per WHO estimates, another 4.1 million people are suffering from latent TB, either asymptomatic or not diagnosed, and the frequency of drug resistance is increasing due to intrinsically linked factors from both host and bacterium. For instance, poor access to TB diagnosis and reduced treatment in the era of the COVID-19 pandemic has resulted in more TB deaths and an 18% reduction in newly diagnosed cases of TB. Additionally, the detection of Mtb isolates exhibiting resistance to multiple drugs (MDR, XDR, and TDR) has complicated the scenario in the pathogen’s favour. Moreover, the conventional methods to detect drug resistance may miss mutations, making it challenging to decide on the treatment regimen. However, owing to collaborative initiatives, the last two decades have witnessed several advancements in both the detection methods and drug discovery against drug-resistant isolates. The majority of them belong to nucleic acid detection techniques. In this review, we highlight and summarize the molecular mechanism underlying drug resistance in Mtb, the recent advancements in resistance detection methods, and the newer drugs used against drug-resistant TB.

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Linezolid: a Promising Agent for the Treatment of Multiple and Extensively Drug-Resistant Tuberculosis

Cited by 4 publications

References 97 publications

Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis

Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis

Mutations and insights into the molecular mechanisms of resistance of Mycobacterium tuberculosis to first-line

Tools to Alleviate the Drug Resistance in Mycobacterium tuberculosis

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