Shortened tuberculosis treatment regimens: what is new?

Silva, Denise Rossato; Mello, Fernanda Carvalho de Queiroz; Migliori, Giovanni Battista

doi:10.36416/1806-3756/e20200009

Cited by 21 publications

(4 citation statements)

References 31 publications

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“…Since 2016, WHO has recommended a shorter regimen for patients with certain conditions owing to the lower cost and higher adherence potential. 83 , 84 Although currently there is no evidence of adherence improvement in shorter regimen, minimizing therapy period will give more confidence of patient to complete the therapy. Shorter regimen also reduces the potency of ADR and diminish therapy-related cost.…”

Section: Discussionmentioning

confidence: 99%

Between Curing and Torturing: Burden of Adverse Reaction in Drug-Resistant Tuberculosis Therapy

Ausi¹,

Santoso²,

Sunjaya³

et al. 2021

PPA

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Section: Discussionmentioning

confidence: 99%

Between Curing and Torturing: Burden of Adverse Reaction in Drug-Resistant Tuberculosis Therapy

Ausi¹,

Santoso²,

Sunjaya³

et al. 2021

PPA

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“…While both kanamycin-containing regimens had superior bactericidal activity during the first 2 weeks of RR/MDR-TB treatment, the addition of bedaquiline allowed for improved killing after 1 month of therapy. Together, these findings provide insight into formulating optimal all-oral bedaquiline-containing regimens with the best potential to shorten duration of MDR-TB treatment (37,44,50). Given that TB-MBLA does not require laboratory procedures associated with culture and the prolonged time to receive a culture-based result, we envision it can be used to make regimen adjustments in the presence of anti-TB drug susceptibility testing results.…”

Section: Discussionmentioning

confidence: 97%

Mycobactericidal Effects of Different Regimens Measured by Molecular Bacterial Load Assay among People Treated for Multidrug-Resistant Tuberculosis in Tanzania

et al. 2021

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Background: Rifampicin or multidrug-resistant-tuberculosis (RR/MDR-TB) treatment has largely transitioned to regimens free of the injectable aminoglycoside component despite the drug class’ purported bactericidal activity early in treatment. We tested whether Mycobacterium tuberculosis (Mtb) killing rates measured by molecular bacterial load assay (TB-MBLA) in sputa correlate with composition of the RR/MDR-TB regimen. Methods: Serial sputa were collected from patients with RR/MDR- and drug-sensitive TB at day 0, 3, 7, 14, and then monthly for 4 months of anti-TB treatment. TB-MBLA was used to quantify viable Mtb 16S rRNA in sputum for estimation of colony-forming-unit per mL (eCFU/mL). Mtb killing rates were compared among regimens using nonlinear-mixed-effects modelling of repeated measures. Results: Thirty-seven patients produced 296 serial sputa: 13 patients received an injectable-containing but bedaquiline-free reference regimen, 9 received an injectable and bedaquiline-containing regimen, 8 received an all-oral bedaquiline-based regimen, and 7 patients were treated for drug-sensitive TB with conventional rifampin/isoniazid/pyrazinamide/ethambutol (RHZE). Compared to the adjusted Mtb killing of -0.17 (95% CI; -0.23 to -0.12) for the injectable-containing but bedaquiline-free reference regimen, the killing rates were -0.62 (95% CI; -1.05 to -0.20) log10 eCFU/mL for the injectable and bedaquiline-containing regimen (p = 0.019), -0.35 (95% CI; -0.65 to -0.13) log10 eCFU/mL for the all-oral bedaquiline-based regimen (p = 0.054), and -0.29 (95% CI; -0.78 to +0.22) log10 eCFU/mL for RHZE (p = 0.332). Conclusion: Mtb killing rates from sputa were higher among patients who received bedaquiline but were further improved with the addition of an injectable aminoglycoside.

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“…Like SQ109, bedaquiline and clofazimine are highly bound to caseum macromolecules ( 35 ), extensively distributed into vascularized tissue and lesion areas ( 32 , 36 ), and showed little to no activity in 14-day EBA trials ( 56 , 57 ). Yet bedaquiline makes critical contributions to novel second-line regimens ( 58 ), and clofazimine is included in numerous ongoing treatment-shortening clinical trials ( 59 ) based on in vitro and preclinical data. Therefore, our results can guide the design of new SQ109-containing regimens based on successful trials that included drugs with similar lesion penetration profiles.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits

Egbelowo

Sarathy

Gausi

et al. 2021

Antimicrob Agents Chemother

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SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109 resistant mutant has been directly isolated thus far, in vitro, in mice or in patients, tentatively attributed to its multiple targets. It is considered as a potential replacement for poorly tolerated components of multidrug-resistant TB regimens. To prioritize SQ109-containing combinations with best potential for cure and treatment shortening, one must understand its contribution against different bacterial populations in pulmonary lesions. Here we have characterized the pharmacokinetics of SQ109 in the rabbit model of active TB and its penetration at the sites of disease: lung tissue, cellular and necrotic lesions, and caseum. A two-compartment model with first-order absorption and elimination described the plasma pharmacokinetics. At the human-equivalent dose, parameter estimates fell within the ranges published for preclinical species. Tissue concentrations were modelled using an "effect" compartment, showing high accumulation in lung and cellular lesion areas with penetration coefficients in excess of 1,000, and lower passive diffusion in caseum after 7 daily doses. These results, together with the hydrophobic nature and high non-specific caseum binding of SQ109, suggest that multi-week dosing would be required to reach steady state in caseum and poorly vascularized compartments, similar to bedaquiline. Linking lesion pharmacokinetics to SQ109 potency in assays against replicating, non-replicating, and intracellular M. tuberculosis showed SQ109 concentrations markedly above pharmacokinetic-pharmacodynamic targets in lung and cellular lesions throughout the dosing interval. IMPORTANCE Drug-resistant tuberculosis (TB) accounts for over 20% of all fatalities due to drug-resistant pathogens. With recently approved drugs and a promising drug candidate pipeline, the challenge faced by clinical developers is prioritization of drug combinations with the best potential to improve cure rates and shorten treatment duration. To this end, one must understand the contribution of each partner drug against different bacterial populations in pulmonary TB lesions. SQ109 is a safe drug candidate in clinical development for the treatment of multidrug resistant TB. It is active against replicating and non-replicating Mycobacterium tuberculosis persisters in vitro, in mouse models and in patients. SQ109 exhibits extremely low frequency of resistance, unprecedented among all TB drugs so far. Here we characterize the pharmacokinetics and activity of SQ109 at the site of TB disease to inform the selection of drug regimens that account for its lesion-centric pharmacokinetic-pharmacodynamic parameters and best leverage its contribution to efficient disease cure.

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Shortened tuberculosis treatment regimens: what is new?

Cited by 21 publications

References 31 publications

Between Curing and Torturing: Burden of Adverse Reaction in Drug-Resistant Tuberculosis Therapy

Between Curing and Torturing: Burden of Adverse Reaction in Drug-Resistant Tuberculosis Therapy

Mycobactericidal Effects of Different Regimens Measured by Molecular Bacterial Load Assay among People Treated for Multidrug-Resistant Tuberculosis in Tanzania

Pharmacokinetics and Target Attainment of SQ109 in Plasma and Human-Like Tuberculosis Lesions in Rabbits

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