Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis

Summary

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 available antituberculosis 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 five groups 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.

Introduction

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 as multidrug-resistant (MDR) are those resistant to at least the two most potent first-line antituberculosis drugs—ie, isoniazid and rifampicin.2, 3, 4, 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, and amikacin.2, 3, 4, 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 patients with incurable tuberculosis (ie, totally drug-resistant 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, 10, 11, 12, 13, 14, 15 or XDR4, 5, 16, 17, 18 tuberculosis, and even in areas with broad-spectrum resistance.9, 13, 17 Clinicians treating patients with XDR tuberculosis are confronted by frustrations similar to those faced before antibiotics were available,¹⁹ when host immunity, fresh air, rest, and good nutrition were relied on for treatment. However, data and clinical experience from the past few years now show drug-resistant tuberculosis can largely be cured with the right combination and rational use of available antituberculosis drugs.2, 20, 21

In this Review we discuss the evidence that rational use of antituberculosis drugs can treat MDR and XDR tuberculosis. Other clinically relevant topics (eg, the need to diagnose MDR tuberculosis as early as possible, the ability of laboratories serving MDR and XDR tuberculosis reference centres to do quality first-line and second-line drug susceptibility testing, and the clinical skills necessary to combine the drug susceptibility testing information about fluoroquinolones, injectables, and ethambutol with a patient's history of prescribed antituberculosis drugs), have been reviewed and discussed elsewhere22, 23, 24, 25 and are not included in this Review. When appropriate, evidence grades for the recommended treatment regimens are given in accordance with the grading system of the Scottish Intercollegiate Guidelines Network.²⁶