Moxifloxacin resistance in the F15/LAM4/KZN extensively drug-resistant strain of Mycobacterium tuberculosis

Dookie, Navisha; Sturm, A. Willem; Moodley, Prashini

doi:10.2147/idr.s65417

Cited by 4 publications

(1 citation statement)

References 18 publications

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“…It is currently approved as an optimum drug for MDR-TB and as a substitute for levofloxacin in the MDR-TB regimen [ 27 ]. Moreover, MFX is an alternative drug for patients who are unable to tolerate the standard DS-TB drug regimen [ 28 ] and also for XDR-TB patients, provided it exhibits a minimum inhibitory concentration (MIC) of <2 mg/L against the isolate [ 29 ]. The structural difference between MFX and other fluoroquinolones ( Figure 1 ), which includes a methoxy group in the C-8 position and the aza-bicyclic group at the C-7 position, contributes to its bactericidal activity, lower MICs, and lower propensity for Mtb to develop resistance against the drug [ 29 ].…”

Section: Novel Anti-mtb Agentsmentioning

confidence: 99%

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

2021

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration and complexity of TB treatment are the main issues leading to treatment failures. Other challenges faced by currently deployed TB regimens include drug-drug interactions, miss-matched pharmacokinetics parameters of drugs in a regimen, and lack of activity against slow replicating sub-population. These challenges underpin the continuous search for novel TB drugs and treatment regimens. This review summarizes new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, mode of resistance generation, and pharmacokinetic properties. As effective TB treatment requires a combination of drugs, the issue of drug-drug interaction is, therefore, of great concern; herein, we have compiled drug-drug interaction reports, as well as efficacy reports for drug combinations studies involving antitubercular agents in clinical development.

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Section: Novel Anti-mtb Agentsmentioning

confidence: 99%

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

2021

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A Review of Moxifloxacin for the Treatment of Drug‐Susceptible Tuberculosis

Naidoo

McIlleron

et al. 2017

The Journal of Clinical Pharma

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Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis (MDR TB) and is being investigated in novel drug regimens with pretomanid, bedaquiline and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid mono-resistance. Evidence suggests that the standard 400mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive inter-individual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is however needed, to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review, the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens.

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Primary Capreomycin Resistance Is Common and Associated With Early Mortality in Patients With Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa

O’Donnell

Pillay

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Capreomycin is a key antimycobacterial drug in treatment of extensively drug-resistant tuberculosis (XDR-TB). Drug susceptibility testing (DST) for capreomycin is not routinely performed in newly diagnosed XDR-TB in South Africa. We performed this study to assess the prevalence, clinical significance, and molecular epidemiology of capreomycin resistance in newly diagnosed XDR-TB patients in KwaZulu-Natal, South Africa. Methods Retrospective cohort study of consecutive XDR-TB patients admitted to a TB referral hospital without prior XDR-TB treatment. A subset of isolates had extended DST (including capreomycin), mutational analysis and IS6110 restriction fragment length polymorphism (RFLP) assays. Results 216 eligible XDR-TB patients were identified. The majority were treated with capreomycin (72%), were young (median age 35.5) and female (56%). 165 (76%) were HIV+, and 109 (66%) were on antiretroviral therapy. A subset of 52 patients had full DST. 47/52 (90.4%) XDR-TB patients were capreomycin resistant. Capreomycin-resistant patients experienced worse mortality and culture conversion than capreomycin susceptible though this difference was not statistically significant. The A1401G mutation in the rrs gene was associated with capreomycin resistance. The majority of capreomycin resistant strains were F15/LAM4/KZN lineage (80%), and clustering was common in these isolates (92.5%). Conclusions Capreomycin resistance is common in patients with XDR-TB in KwaZulu-Natal, is predominantly due to ongoing province-wide transmission of a highly resistant strain, and is associated with high mortality. Capreomycin should be included in routine DST in all XDR-TB patients. New drug regimens that do not include injectable agents should be operationally tested as empiric treatment in XDR-TB.

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Moxifloxacin resistance in the F15/LAM4/KZN extensively drug-resistant strain of Mycobacterium tuberculosis

Cited by 4 publications

References 18 publications

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

A Review of Moxifloxacin for the Treatment of Drug‐Susceptible Tuberculosis

Primary Capreomycin Resistance Is Common and Associated With Early Mortality in Patients With Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa

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