Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial

Velásquez, Gustavo E.; Brooks, Meredith B.; Coit, Julia; Pertinez, Henry; Vasquez, Dante Vargas; Garavito, Epifanio Sánchez; Calderón, Róger; Jiménez, Judith; Tintaya, Karen; Peloquin, Charles A.; Osso, Elna; Tierney, Dylan B.; Seung, Kwonjune J.; Lecca, Leonid; Davies, Geraint R.; Mitnick, Carole D.

doi:10.1164/rccm.201712-2524oc

Cited by 84 publications

(69 citation statements)

References 40 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For rifampin and rifapentine, plasma exposures higher than those achieved with current doses result in improved antituberculosis activity and appear to be relatively safe. Recent and ongoing clinical studies are likely to broadly redefine the optimal dosing strategies for these rifamycins and other drugs in treatment and preventive therapy regimens [19][20][21][22][23][24]. Evidence is needed to inform appropriate doses for tuberculosis at sites where penetration of the drugs into the diseased compartments is limited such as tuberculous pericarditis and tuberculous meningitis [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Current research toward optimizing dosing of first-line antituberculosis treatment

McIlleron

Chirehwa

2018

Expert Review of Anti-infective Therapy

View full text Add to dashboard Cite

Introduction: Drug concentrations in tuberculosis patients on standard regimens vary widely with clinically important consequences.Areas covered: We review the available literature identifying factors correlated with pharmacokinetic variability of antituberculosis drugs. Based on population pharmacokinetic models and the weight, height, and sex distributions in a large data base of African tuberculosis patients, we propose simplified weight-based doses of the available fixed dose combination(FDC) for adults with drug susceptible tuberculosis. Emerging studies will support optimized weight-based dosing for children. Other sources of important pharmacokinetic variability include genetic variants, drug-drug interactions, formulation quality, and methods of preparation and administration.Expert commentary: Optimized weight band-based dosing will result in more equitable distribution of drug exposures by weight. The use of high doses of isoniazid in patients with drug-resistant tuberculosis would be safer and more effective if a feasible test was developed to allow stratified dosing according to acetylator type. There is an urgent need for more suitable formulations of many second-line drugs for children. The adoption of new technologies and efficient FDC design may allow further advances for patients and treatment programs. Lastly, current efforts to ensure adequate quality of antituberculosis drug products are not preventing the use of substandard products to treat patients with tuberculosis.

show abstract

Section: Introductionmentioning

confidence: 99%

Current research toward optimizing dosing of first-line antituberculosis treatment

McIlleron

Chirehwa

2018

Expert Review of Anti-infective Therapy

View full text Add to dashboard Cite

show abstract

“…Several studies are evaluating higher doses of rifampicin as a strategy for TB treatment shortening. Rifampicin used at a dose of 20mg/kg did not demonstrate any difference in treatment outcomes compared to standard dosing; however, at 35mg/kg, faster sputum conversion in liquid medium was observed with no increased risk of toxicities compared to the standard dose used in the controls [9,10]. This suggests that bold, rather than modest, increases in rifampicin dosing will be needed for treatment shortening.…”

Section: Rifampicinmentioning

confidence: 86%

Pharmacokinetic and pharmacodynamic considerations of rifamycin antibiotics for the treatment of tuberculosis

Sekaggya-Wiltshire

Dooley

2019

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

“…Results achieved in animal models indicate that a higher dose of rifampicin of 30-35 mg/kg may enable a treatment regimen of 1-2 weeks for filarial diseases of humans [19,20]. The safety profile of high rifampicin doses has been evaluated in human clinical trials against tuberculosis and appears to be safe up to a dose of 20 mg/kg and some additional studies also confirmed a safe profile with higher doses of 35 mg/kg [29][30][31][32].…”

Section: Fig 3 An11251 and Doxycycline Combination Therapy Provides mentioning

confidence: 94%

In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis

Ehrens¹,

Lunde²,

Jacobs³

et al. 2020

PLoS Negl Trop Dis

View full text Add to dashboard Cite

The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontisinfected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment.These results indicate that AN11251 is superior to doxycycline and comparable to highdose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10-14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis.PLOS Neglected Tropical Diseases | https://doi.Onchocerciasis and lymphatic filariasis are human filarial tropical diseases, which can cause blindness and severe dermatitis (onchocerciasis) or lymphedema and hydrocele (lymphatic filariasis). Current strategies to eliminate these diseases include the mass drug administration (MDA) of drugs that target the progeny of the filariae, the microfilariae, and temporarily inhibit filarial embryogenesis and, therefore, the transmission of the disease. However, MDA has several limitations that delay the goal of elimination including the lack of a drug with a short term regimen and a potent macrofilaricidal effect. As an alternative approach, the antibiotic doxycycline has been proven to be effective in depleting Wolbachia endosymbionts from adult filariae, which then leads to permanent sterilization and death of the adult worms. Due to contraindications for doxycycline and prolonged treatment regimen of at least 4 weeks, there is an urgent need for new anti-filarial drugs with an improved safety profile and shorter regimens. The current study demonstrates that the boron-pleuromutilin derivative AN11251 provides an excellent in vivo anti-Wolbachia depletion in the Litomosoides sigmodontis filarial mouse model that is superior to doxycycline and comparable to rifampicin, allowing for regimens as short as 10-14 days. Combination with doxycycline for 7 da...

show abstract

Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial

Abstract: Our findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01408914) .

Cited by 84 publications

References 40 publications

Current research toward optimizing dosing of first-line antituberculosis treatment

Current research toward optimizing dosing of first-line antituberculosis treatment

Pharmacokinetic and pharmacodynamic considerations of rifamycin antibiotics for the treatment of tuberculosis

In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis

Contact Info

Product

Resources

About