Tuberculosis treatment and management—an update on treatment regimens, trials, new drugs, and adjunct therapies

Zumla, Alimuddin; Chakaya, Jeremiah; Centis, Rosella; Mwaba, Peter; Bates, Matthew; Kapata, Nathan; Nyirenda, Thomas; Chanda, Duncan; Mfinanga, Sayoki; Höelscher, Michael; Maeurer, Markus; Migliori, Giovanni Battista

doi:10.1016/s2213-2600(15)00063-6

Cited by 189 publications

(152 citation statements)

References 73 publications

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“…In 2014, the World Health Organization reported 9.6 million new cases of TB [2], infection caused by inhalation of aerosol particles containing Mycobacterium tuberculosis (MTB) bacilli [1]. The inhaled bacilli are phagocytosed by alveolar macrophages, which triggers a series of events that can lead to either control of the infection, i.e., latent TB, or progression to an active form of the disease [1].…”

Section: Introductionmentioning

confidence: 99%

“…Severe side effects are frequently reported that, in many cases, lead to therapeutic noncompliance. Therefore, other alternatives are being actively searched to shorten the duration, and perhaps the modality, of treatment [2]. Shortening treatment duration would permit minimising possible side effects in organs such as the liver and kidneys, and avoiding the emergence of resistant TB species.…”

Section: Introductionmentioning

confidence: 99%

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Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

et al. 2016

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Tuberculosis remains a major global health problem and alternative therapeutic approaches are needed. Considering the high prevalence of lung tuberculosis (80% of cases), the pulmonary delivery of antitubercular drugs in a carrier system capable of reaching the alveoli, being recognised and phagocytosed by alveolar macrophages (mycobacterium hosts), would be a significant improvement to current oral drug regimens. Locust bean gum (LBG) is a polysaccharide composed of galactose and mannose residues, which may favour specific recognition by macrophages and potentiate phagocytosis. LBG microparticles produced by spray-drying are reported herein for the first time, incorporating either isoniazid or rifabutin, first-line antitubercular drugs (association efficiencies >82%). Microparticles have adequate theoretical properties for deep lung delivery (aerodynamic diameters between 1.15 and 1.67 µm). The cytotoxic evaluation in lung epithelial cells (A549 cells) and macrophages (THP-1 cells) revealed a toxic effect from rifabutin-loaded microparticles at the highest concentrations, but we may consider that these were very high comparing with in vivo conditions. LBG microparticles further evidenced strong ability to be captured by macrophages (percentage of phagocytosis >94%). Overall, the obtained data indicated the potential of the proposed system for tuberculosis therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

et al. 2016

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“…Two billion people are latently infected with this organism, and in 10% of them, it reactivates to active TB in their lifetime (1). Currently, treatments require 6 months of combination therapy with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol for active TB and 9 months of INH or 3 months of rifapentine (RFP) and INH for latent TB (2,3). Active and latent TB infections comprise mixtures of cellular and caseous granulomas, with tubercle bacilli ranging from actively replicating (AR) to dormant nonreplicating (NR) stages (4).…”

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confidence: 99%

Mycobacterium tuberculosis Is Selectively Killed by Rifampin and Rifapentine in Hypoxia at Neutral pH

Iacobino

Piccaro

Giannoni

et al. 2017

Antimicrob Agents Chemother

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The activities of rifampin, rifapentine, bedaquiline, PA-824, clofazimine, nitazoxanide, isoniazid, amikacin, moxifloxacin, niclosamide, thioridazine, and pyrazinamide were tested against nonreplicating (dormant) Mycobacterium tuberculosis H37Rv under conditions of hypoxia at pHs 5.8 and 7.3, mimicking environments of cellular granulomas and caseous granulomas, respectively. At pH 5.8, several drugs killed dormant bacilli, with the best being rifampin and rifapentine. At pH 7.3, only rifampin and rifapentine efficiently killed dormant bacilli, while all other drugs showed little activity.KEYWORDS Mycobacterium tuberculosis, dormancy, hypoxia, killing, pH, rifampin, rifapentine, tuberculosis T he etiologic agent of tuberculosis (TB) is Mycobacterium tuberculosis. Two billion people are latently infected with this organism, and in 10% of them, it reactivates to active TB in their lifetime (1). Currently, treatments require 6 months of combination therapy with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol for active TB and 9 months of INH or 3 months of rifapentine (RFP) and INH for latent TB (2, 3). Active and latent TB infections comprise mixtures of cellular and caseous granulomas, with tubercle bacilli ranging from actively replicating (AR) to dormant nonreplicating (NR) stages (4). In cellular granulomas, replicating bacilli are killed by current therapy, while in low vascularized caseous granulomas, low oxygen pressure restricts the growth from the AR to the NR stage in their hypoxic centers, enabling M. tuberculosis to move into a dormant drug-refractory state.The pH of the phagolysosomes of activated macrophages present in cellular granulomas is acidic (5), while in necrotic centers of hypoxic cholesterol/triacylglycerol-rich caseous granulomas, where dormant M. tuberculosis lives, the pH is 7.2 to 7.5 (6-8). No information on drug activity against NR M. tuberculosis grown in hypoxic neutral conditions is known. In this study, we investigated the growth patterns of NR M. tuberculosis at different pHs and measured the activities of 12 drugs against NR cells under hypoxic conditions at pHs 5.8 and 7.3, mimicking the environments of cellular granulomas and caseous granulomas, respectively.Briefly, M. tuberculosis strain H37Rv was grown at 37°C for 40 days in 20-by 125-mm screw-cap tubes containing Dubos-Tween-albumin broth (DTAB) as previously described (9-11), but in the present study, the DTAB was adjusted to pHs 5. 8, 6.6, 7.0, 7.4, and 7.6. For preparation of NR cells, log-phase cultures were diluted in DTAB and incubated in tubes with the caps tightly screwed and tight rubber caps put under the screw caps. Growth in the tubes was monitored by measuring pH, optical density at 600 nm, and CFU/ml on Middlebrook 7H10 (7H10) agar plates incubated at 37°C for 3 weeks. To determine drug activity against NR cells, 12-and 19-day-old hypoxic cultures (H12 and H19, respectively) were incubated with drugs for 7, 14, and 21 days. Drugs

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“…Moreover, DST is often too expensive, especially in high-burden countries, and in many settings it is neglected because of the lack of SLD [73,74]. In general, treatment for MDR-TB can extend up to 2 years after microbiologic culture conversion and relies on more toxic, less efficacious second-or third-line agents, many of which are even more scarce than frontline drugs in affected areas [75]. Although adherence to therapeutic programs is often impossible for immigrants as they are often lost in follow-up, at least five drugs (including an injectable agent) should be given for an "intensive phase" of up to 8 months.…”

Section: Mdr and Xdr-tb Management Issuesmentioning

confidence: 99%

The Impact of Tuberculosis among Immigrants: Epidemiology and Strategies of Control in High-Income Countries—Current Data and Literature Review

Contini¹,

Maritati²,

Nuzzo³

et al. 2017

People's Movements in the 21st Century - Risks, Challenges and Benefits

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A significant reappearance of tuberculosis (TB) was observed in industrialized countries during the last two decades. This is due to the spread of HIV infection itself and to today's migratory phenomenon as a consequence of wealth disparity, poverty, wars and political persecutions. This proportion is expected to increase and represents an important cause of the overall resurgence of the TB epidemic and drug-resistant TB in Western Europe and the USA. TB is currently one of the leading causes of death worldwide and a health problem in high-income countries. Although WHO global TB report 2015 with its "STOP TB" strategy has the goal to eliminate TB as a public health problem by 2050, TB shows no signs of disappearing despite some decline in high-income countries. In order to intensify the fights against this deadly disease, further efforts should be aimed to improve examination/detection processes to accurately determine all kinds of TB, and how best to enhance TB control through a coordinated medical screening program of migrants for active TB. Migration in itself is not a definitive risk for TB. Stressful living condition, social isolation, poverty, political fear/persecution, and difficulties to access to health care can expose these individuals to the risk of TB infection during and after the migration process. This chapter aims to discuss and highlight all these issues.

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Tuberculosis treatment and management—an update on treatment regimens, trials, new drugs, and adjunct therapies

Cited by 189 publications

References 73 publications

Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

Mycobacterium tuberculosis Is Selectively Killed by Rifampin and Rifapentine in Hypoxia at Neutral pH

The Impact of Tuberculosis among Immigrants: Epidemiology and Strategies of Control in High-Income Countries—Current Data and Literature Review

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