Articles cited in this Review were obtained though searches of PubMed and Google Scholar covering the period from November 1, 2000, until July 15, 2010. The keywords included “TB”, “drug-resistant TB”, “MDR-TB”, and “XDR-TB”. Reference lists of these articles were then reviewed to identify additional studies. The US Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report was searched from January 1, 1989, until July 15, 2010 for reports describing MDR and XDR
ReviewBest drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis
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
Section snippets
Treatment overview
There are several basic rules for the management of patients with MDR or XDR tuberculosis. The recommended regimen is a combination of at least four drugs to which the M tuberculosis isolate is likely to be susceptible, although more than four might be necessary. Drugs are chosen with a stepwise selection process through five groups of antituberculosis drugs (table), on the basis of efficacy, safety, and cost. The duration of the intensive phase of treatment (when an injectable drug is given)
Group one: first-line antituberculosis drugs
The first group includes the four key drugs that make up the initial phase of the ideal short-course chemotherapy regimen: isoniazid, rifampicin, pyrazinamide, and ethambutol.2, 20, 21 Most patients with MDR or XDR tuberculosis will have already been mismanaged with one or more cycles of combined drugs, including pyrazinamide and ethambutol.3 On the basis of this assumption and the low reliability of the susceptibility tests to ethambutol and pyrazinamide,21, 27 resistance to these two drugs
Group two: fluoroquinolones
Resistance to fluoroquinolones increases the risk of treatment failure and death in patients with MDR or XDR tuberculosis.47 Fluoroquinolones are the mainstay of treatment for patients with MDR or XDR tuberculosis and deliver better clinical outcomes than do the drugs in the other groups.2, 3, 8, 12 Because all fluoroquinolones share a genetic target—the gyrA gene48—the use of only one of them is justified.2, 20, 21
Group three: injectable antituberculosis drugs
This group of drugs is another mainstay in the treatment of MDR and XDR tuberculosis and includes the aminoglycosides (streptomycin, kanamycin, and amikacin) and the polypeptides (capreomycin and viomycin; unfortunatley viomycin is unavailable in most countries). The injectables are bactericidal with high extracellular activity, but some intracellular activity has also been shown,56 which can be explained by their method of action. The aminoglycosides inhibit protein synthesis through
Group four: second-line antituberculosis drugs
This group includes compounds from three classes of drugs: the thioamides (ethionamide and protionamide), cycloserine or its derivative terizidone (a double molecule of cycloserine, which has nearly the same action but is cheaper), and aminosalicylic acid. Several clinical studies have assessed the efficacy and effectiveness of this group of second-line antituberculosis drugs. Because they belong to different drug classes with diverse genetic targets, the use of more than one of these drugs, if
Group five drugs
Group five drugs are a very heterogeneous group of drugs, which are poorly studied in vivo in human beings or have low effectiveness or high toxicity. Therefore, the drugs in group five are thought of as minor or adjuvant drugs;2, 20, 21 each one should be counted as only half of one of the four basic drugs needed to treat MDR and XDR tuberculosis. Therefore, when it is really necessary to use a drug from this group, at least two should be chosen. On the basis of effectiveness criteria,
Conclusions
In many cases, both MDR and XDR tuberculosis can be cured with the right combination of available antituberculosis drugs. Every case of tuberculosis, including those caused by M tuberculosis strains with a broad drug-resistance profile, can probably be treated if the available antituberculosis drugs are used rationally.8 Several factors should be considered when choosing the appropriate drug, including availability of the drug, the rationale to introduce a given drug, the patient's resistance
Search strategy and selection criteria
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