Fluoroquinolones, the Cornerstone of Treatment of Drug-Resistant Tuberculosis: A Pharmacokinetic and Pharmacodynamic Approach

Pranger, Arianna D.; Alffenaar, Jan-Willem; Aarnoutse, R.E.

doi:10.2174/138161211797470200

Cited by 25 publications

(24 citation statements)

References 134 publications

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“…Although there is no consensus on the precise f AUC 0–24 /MIC ratio that best predicts in vivo efficacy, ratios of >100 at the upper end of the wild-type distribution are likely required to maximize clinical success (44, 45). Given that the currently recommended dose of AFX is unusually low (probably because of a narrow clinical indication) compared with the doses of the other fluoroquinolones used to treat tuberculosis, the target f AUC 0–24 /MIC of >100 at an increased dose is likely achievable, but this would have to be evaluated in clinical trials, where side effects would have to be monitored carefully.…”

Section: Discussionmentioning

confidence: 99%

Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin

Wang

Chen

et al. 2016

Antimicrob Agents Chemother

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f Antofloxacin (AFX) is a novel fluoroquinolone that has been approved in China for the treatment of infections caused by a variety of bacterial species. We investigated whether it could be repurposed for the treatment of tuberculosis by studying its in vitro activity. We determined the wild-type and non-wild-type MIC ranges for AFX as well as ofloxacin (OFX), levofloxacin (LFX), and moxifloxacin (MFX), using the microplate alamarBlue assay, of 126 clinical Mycobacterium tuberculosis strains from Beijing, China, of which 48 were OFX resistant on the basis of drug susceptibility testing on Löwenstein-Jensen medium. The MIC distributions were correlated with mutations in the quinolone resistance-determining regions of gyrA (Rv0006) and gyrB (Rv0005). Pharmacokinetic/pharmacodynamic (PK/PD) data for AFX were retrieved from the literature. AFX showed lower MIC levels than OFX but higher MIC levels than LFX and MFX on the basis of the tentative epidemiological cutoff values (ECOFFs) determined in this study. All strains with non-wild-type MICs for AFX harbored known resistance mutations that also resulted in non-wild-type MICs for LFX and MFX. Moreover, our data suggested that the current critical concentration of OFX for Löwenstein-Jensen medium that was recently revised by the World Health Organization might be too high, resulting in the misclassification of phenotypically non-wildtype strains with known resistance mutations as wild type. On the basis of our exploratory PK/PD calculations, the current dose of AFX is unlikely to be optimal for the treatment of tuberculosis, but higher doses could be effective.

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Section: Discussionmentioning

confidence: 99%

Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin

Wang

Chen

et al. 2016

Antimicrob Agents Chemother

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“…71 As a broad-spectrum antibacterial, DC-159a exhibits activity against Streptococcus spp., Staphylococcus spp. 72 and several other clinically relevant bacteria, 73 as well as having potent activity against fluoroquinolone-resistant strains of bacteria including M. tuberculosis H37Rv. 74,75 In a mouse model of M. tuberculosis infection, DC-159a was found to be more effective than moxifloxacin at bacterial clearance during initial and extended treatment.…”

Section: Quinolonesmentioning

confidence: 99%

New tuberculosis drug leads from naturally occurring compounds

Quan

Nagalingam

Payne

et al. 2017

International Journal of Infectious Diseases

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Tuberculosis (TB) continues to be a significant cause of mortality and morbidity worldwide. An estimated 2 billion individuals are infected with Mycobacterium tuberculosis and annually there are approximately 10 million new cases of clinical TB and 1.5 million deaths. Currently available drugs and vaccines have had no significant impact on TB control. In addition, the emergence of drug resistant TB is considered a public health crisis, with some strains now resistant to all available drugs. Unfortunately, the growing burden of antibiotic resistance is coupled with decreased effort in the development of new antibiotics. Natural sources are attractive starting points in the search for anti-tubercular drugs because they are extremely rich in chemical diversity and have privileged antimicrobial activity. This review will discuss recent advances in the development of TB drug leads from natural products, with a particular focus on anti-mycobacterial compounds in late-stage preclinical and clinical development.

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“…Fluoroquinolones are essential in drug-resistant TB (DR-TB) treatment, but pharmacokinetic and safety data (including data on potential QT interval prolongation) for children are limited (3)(4)(5)(6). South African DR-TB treatment guidelines were revised during 2012 to recommend levofloxacin (Lfx) and moxifloxacin (Mfx) instead of ofloxacin (Ofx) in children.…”

mentioning

confidence: 99%

Pharmacokinetics of Ofloxacin and Levofloxacin for Prevention and Treatment of Multidrug-Resistant Tuberculosis in Children

Thee

Garcia-Prats

McIlleron

et al. 2014

Antimicrob Agents Chemother

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dLimited data on fluoroquinolone pharmacokinetics and cardiac effects in children exist. Among 22 children receiving drug-resistant tuberculosis prophylaxis or treatment, serum concentrations following oral doses of levofloxacin (15 mg/kg of body weight) and ofloxacin (20 mg/kg) were lower than those expected from existing pediatric data, possibly due to differences in the formulations (crushed tablets). Drug exposures were lower than those in adults following standard doses and below the proposed pharmacodynamic targets, likely due to more rapid elimination in children. No QT prolongation was observed. Multidrug-resistant tuberculosis (MDR-TB) (i.e., resistance to rifampin and isoniazid) is an emerging epidemic with an estimated 63,000 pediatric cases per year (1, 2). Fluoroquinolones are essential in drug-resistant TB (DR-TB) treatment, but pharmacokinetic and safety data (including data on potential QT interval prolongation) for children are limited (3-6). South African DR-TB treatment guidelines were revised during 2012 to recommend levofloxacin (Lfx) and moxifloxacin (Mfx) instead of ofloxacin (Ofx) in children. Due to tablet sizes, children Ͼ8 years receive Mfx and children Ͻ8 years receive Lfx for prevention or treatment of DR-TB. We aimed to characterize the pharmacokinetics and cardiac effects of Ofx and Lfx in children Ͻ8 years of age.A prospective crossover intensive pharmacokinetic sampling study was conducted at Brooklyn Chest Hospital and Tygerberg Children's Hospital in Cape Town, South Africa from May 2012 through March 2013. Children aged 3 months to 8 years routinely started on either Ofx or Lfx for the prevention or treatment of MDR-TB were eligible. Exclusion criteria were a hemoglobin level of Ͻ8 g/dl or a weight of Ͻ5 kg. Child contacts (Ͻ5 years or HIV infected) of infectious MDR-TB cases without TB disease received preventive therapy, including 20 mg/kg of body weight Ofx or 15 mg/kg Lfx daily for 6 months. Children with MDR-TB received MDR-TB treatment based on World Health Organization recommendations (7). South African Medicines Control Council-approved tablets of Ofx (Tarivid, 200-mg tablets; Sanofi-Aventis, Midrand, South Africa) and Lfx (250-mg tablets; Cipla, Cape Town, South Africa) were used.Two pharmacokinetic samplings were done, alternately for Ofx and Lfx, both at steady state. Exact doses of Ofx of 20 mg/kg and of Lfx of 15 mg/kg were used, and the tablets were broken accordingly and weighed to the nearest 0.1 mg. After an overnight fast, tablets were given whole or crushed and suspended in water, and the dose taken was observed. Blood samples were collected predose and at 1, 2, 4, 6, and 8 h after dosing in EDTA-containing tubes and centrifuged, and plasma was separated and frozen within 30 min at Ϫ80°C. Lfx concentrations were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay developed in the Division

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Fluoroquinolones, the Cornerstone of Treatment of Drug-Resistant Tuberculosis: A Pharmacokinetic and Pharmacodynamic Approach

Cited by 25 publications

References 134 publications

Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin

Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin

New tuberculosis drug leads from naturally occurring compounds

Pharmacokinetics of Ofloxacin and Levofloxacin for Prevention and Treatment of Multidrug-Resistant Tuberculosis in Children

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