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Review

Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis
José A Caminero, Giovanni Sotgiu, Alimuddin Zumla, Giovanni Battista Migliori

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are generally thought to have high mortality rates. However, many cases can be treated with the right combination and rational use of availableantituberculosis drugs. This Review describes the evidence available for each drug and discusses the basis for recommendations for the treatment of patients with MDR and XDR tuberculosis. The recommended regimen is the combination of at least four drugs to which the Mycobacterium tuberculosis isolate is likely to be susceptible. Drugs are chosen with a stepwise selection process through fivegroups on the basis of efficacy, safety, and cost. Among the first group (the oral first-line drugs) high-dose isoniazid, pyrazinamide, and ethambutol are thought of as an adjunct for the treatment of MDR and XDR tuberculosis. The second group is the fluoroquinolones, of which the first choice is high-dose levofloxacin. The third group are the injectable drugs, which should be used in the following order:capreomycin, kanamycin, then amikacin. The fourth group are called the second-line drugs and should be used in the following order: thioamides, cycloserine, then aminosalicylic acid. The fifth group includes drugs that are not very effective or for which there are sparse clinical data. Drugs in group five should be used in the following order: clofazimine, amoxicillin with clavulanate, linezolid,carbapenems, thioacetazone, then clarithromycin.

Lancet Infect Dis 2010; 10: 621–29 Servicio de Neumología, Hospital General de Gran Canaria, Las Palmas, Canary Islands, Spain (J A Caminero MD); International Union Against Tuberculosis and Lung Disease, Paris, France (J A Caminero); Hygiene and Preventive Medicine Institute, University of Sassari, Sassari, Italy (G Sotgiu PhD); Department ofInfection, University College London Medical School, London, UK (A Zumla FRCP); and WHO Collaborating Centre for TB and Lung Diseases, Fondazione S Maugeri, Care and Research Institute, Tradate, Italy (G B Migliori MD) Correspondence to: Dr José A Caminero, Servicio de Neumología, Hospital General de Gran Canaria, Barranco de la Ballena s/n 35010, Las Palmas de GC, Spain jcamlun@gobiernodecanarias. orgIntroduction
The period between 1950 and 1970 was a turning point in the battle against tuberculosis: most of the current antituberculosis drugs were discovered and new therapeutic regimens made tuberculosis a curable disease.1 The initial optimism of the tuberculosis-control community began to wane when drug-resistant Mycobacterium tuberculosis strains emerged. Tuberculosis strains classified asmultidrug-resistant (MDR) are those resistant to at least the two most potent first-line antituberculosis drugs—ie, isoniazid and rifampicin.2–5 Extensively drug-resistant (XDR) tuberculosis strains are resistant to either isoniazid or rifampicin (like MDR tuberculosis), any fluoroquinolone, and at least one of three second-line antituberculosis injectable drugs—ie, capreomycin, kanamycin, andamikacin.2–5 The treatment of tuberculosis becomes more complicated as the antibiotic resistance profile of M tuberculosis broadens, especially in the case of MDR and XDR tuberculosis. MDR and XDR tuberculosis are generally thought to have high mortality rates. With the exception of the fluoroquinolones, no new antituberculosis drug has been introduced in the past 45 years.2,6 The notion of patientswith incurable tuberculosis (ie, totally drugresistant tuberculosis) is now regularly referred to.7 The probability of successful treatment further decreases with the emergence of new drug-resistant strains. However, prudent use of combinations of available drugs could improve chances of cure,8 even in patients with MDR2,3,9–15 or XDR4,5,16–18 tuberculosis, and even in areas with broad-spectrum...