and 2 of drug development as of the first quarter of the year 2023 and several ongoing clinical trials evaluating novel combinations of medicines in different regimens, there is prospect for even shorter, safer and more effective treatments in the near future [8]. However, emergence of Mycobacterium tuberculosis drug resistance is challenging the success of anti-TB therapies [9]. Recent history teaches us that soon after the marketing of novel anti-TB medicines drug-resistant strains of M. tuberculosis can be found [10, 11]. In this chapter we present a brief history of the treatments against TB, we inform about drugs and their mode of action and we review current treatment recommendations against DS-TB and DR-TB. History of the medical treatment of TB The sanatorium movement, from the Latin word sanare, “to heal”, started decades before the discovery of M. tuberculosis by Robert Koch in 1882 (figure 1). In 1840, George Bodington, a British physician, published an essay entitled “On the Treatment and Cure of Pulmonary Consumption” in which he advocated for a treatment based on fresh air and a balanced diet [12]. In 1862, Hermann Brehmer inaugurated the first high-altitude sanatorium specifically dedicated to PTB patients at Görbersdorf (now Sokołowsko in Poland) [13]. Though the pathophysiology of TB was not yet understood at that time, a physiological substratum could be found in bed rest. Gravity indeed affects the distribution of ventilation and blood flow in the lung. Lying in a horizontal position could help by reducing oxygen tension in the apices and therefore the multiplication of the TB bacilli. This process would specially be emphasised at high altitudes given the low amount of oxygen in the air [14]. With the advent of the sanatorium era, several therapeutic protocols were introduced to treat TB [15, 16]. In 1881, Professor Jaccoud (France) published “The Curability and Treatment of Pulmonary Phthisis”, in which he described the most popular TB treatments at that time [17]. Associated with hygienic measures, Jaccoud mentioned among others the use of chest massages, salts of iron, cod liver oil, arsenic, antimony, quinine salts and inhalations of carbolic acid, iodine, creosote and turpentine [18]. TB treatment by gold compounds became popular in the 1920s based on the fact that gold cyanide was found effective in vitro against cultures of TB bacilli, despite its absence of effectiveness in vivo [19]. Medical treatments were also supported by surgical procedures. These included, for instance, artificial pneumothorax proposed by Forlanini since 1882, lung resection since Block’s works in 1883, thoracoplasty first performed by De Cérenville in 1885 and phrenic nerve crush proposed by Stuertz in 1911 [20]. Though frequently used in selected patients, none of these interventions was ever properly evaluated to assess their efficacy. Overall, no scientific evidence exists that sanatorium treatment had any efficacy against TB, and with the discovery of effective antibiotic therapies, sanatoria became progressively obsolete [21, 22]. In 1943, streptomycin, purified from Streptomyces griseus, was isolated in the laboratory of Selman Waksman at Rutgers University (USA) [23]. In 1944, a TB patient was declared cured after a streptomycin treatment, soon followed by other case series [24, 25]. In 1948, the British Medical Research Council conducted the first large-scale clinical trial to assess the efficacy of streptomycin [26]. The results showed efficacy at 6 months (7% mortality rate in the streptomycin arm compared to 27% in the “bed rest” arm), but not after a 5-year follow up (58% in the streptomycin arm compared to 76% in the “bed rest” arm), and the majority of M. tuberculosis strains from streptomycin-treated patients developed streptomycin resistance [27]. Available anti-TB medicines Streptomycin discovery and development was soon followed by the advent of several anti-TB drugs in the late 1940s and 1950s [28]. Researchers rapidly demonstrated the benefits of 118 https://doi.org/10.1183/2312508X.10024622 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY