Global challenges regarding the treatment of multidrug drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) include factors related to their diagnosis and treatment. The World Health Organization (WHO) states in their 2011 report on Global Tuberculosis Control that about 50,000 cases of MDR-TB were reported to the organization in 2010, which is equivalent to only 16% of the estimated 290,000 actual cases of MDR-TB worldwide. A WHO global surveillance report indicated that from 2002-2007, about 50% of reported MDR-TB cases were from China and India; the third most prevalent country was the Russian Federation, with about 7% of cases. The actual prevalence of MDR-TB is probably underestimated owing to lack of uniform drug susceptibility testing.
The efficacy of second-line agents, medication access, medication-related adverse effects, and concern about medication adherence during prolonged therapy are all important factors to consider. There have been no randomized controlled trials comparing second-line agents for MDR-TB, and data on the treatment of XDR-TB are extremely limited. This article discusses agents available for MDR-TB treatment in patients who are not co-infected with HIV and the recommendations included in the WHO guidelines.
The typical first-line treatment for non-drug-resistant TB consists of isoniazid, rifampin, ethambutol, and pyrazinamide. The WHO defines MDR-TB as resistance to 2 of the 4 first-line anti-TB medications (isoniazid and rifampin). XDR-TB is defined as resistance to both of these agents, plus any fluoroquinolone and at least 1 of 3 injectable medications (amikacin, kanamycin, or capreomycin). Patients with non-drug-resistant TB have an approximate 90% cure rate when treated with a total of 4 drugs over 6 months. Patients treated for MDR-TB have a 60%-75% cure rate with a 5-drug regimen given for a minimum of 20 months.
Preferred agents not approved by the US Food and Drug Administration that are used to treat MDR-TB include fluoroquinolones (eg, moxifloxacin and levofloxacin) and aminoglycosides (amikacin, capreomycin, and kanamycin). Additional agents used (although not recommended as initial MDR-TB treatment) are linezolid, amoxicillin/clavulanate, clarithromycin, and imipenem. The WHO guidelines recommend the following 5-agent treatment regimen for MDR-TB: pyrazinamide; a fluoroquinolone; a parenteral agent (typically amikacin or kanamycin); ethionamide (or prothionamide); and either cycloserine or para-aminosalicylic acid, with preference for cycloserine.
For patients who have not previously received MDR-TB treatment, the intensive phase of therapy should last a minimum of 8 months (including the parenteral aminoglycoside), with a total treatment duration of at least 20 months. Because data are limited data, there is no recommended treatment regimen for XDR-TB. Regimen design is similar to that for MDR-TB, and it is important to perform drug susceptibility testing to guide therapy. The WHO recommends monitoring MDR-TB treatment through monthly sputum-smear microscopy and culture to identify early treatment failure.
As the basis of their MDR-TB treatment recommendations, the WHO guidelines focus on a pooled meta-analysis of data from 3 unpublished systematic reviews (The Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB. Unpublished data). On the basis of this meta-analysis, aminoglycosides are the preferred parenteral agents, with no superior efficacy demonstrated among amikacin, capreomycin, and kanamycin. The cure rate was higher with ethionamide than with cycloserine, and with cycloserine than para-aminosalicylic acid. However, in patients previously treated for MDR-TB, ethionamide was associated with little efficacy. Among the additional agents (linezolid, macrolides, and imipenem), there was no difference in cure rates; however, patients treated with these agents had worse outcomes that were attributed to confounding factors (The Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB. Unpublished data).
Dosing regimens for MDR-TB agents vary in the literature, and use of the lowest efficacious dose is important, because patients are at an increased risk for medication-related adverse effects owing to the prolonged treatment courses. Trials of oral levofloxacin have been dosed at 300 mg/day or 500 mg/day, while oral moxifloxacin has been studied at 400 mg/day. Potential adverse effects associated with fluoroquinolones include but are not limited to central nervous system effects (eg, tremor, confusion, dizziness, and seizures), QTc prolongation, gastrointestinal disturbances, and tendon rupture.[5,6]
Amikacin and kanamycin are typically dosed at 15 mg/kg/day or 25 mg/kg 3 times per week intravenously, and both dosing regimens seem to be similar in limiting potential adverse effects with weekly serum level monitoring. Potential adverse effects of aminoglycosides include but are not limited to nephrotoxicity and ototoxicity. Varying doses of oral linezolid have been studied, including once-daily doses of 300 mg and 600 mg.[8,9] Bone marrow suppression, peripheral neuropathy, and neurotoxicity are all potential adverse effects of linezolid[8,9]; lower doses or once-daily administration has been considered in an attempt to minimize their occurrence or severity. Appropriate monitoring and patient counseling on potential medication-related adverse effects is essential for all MDR-TB agents.
The following is a potential empiric treatment regimen for a non-HIV-infected adult with normal renal function who is being treated for MDR-TB:
- Moxifloxacin 400 mg/day orally;
- Amikacin 25 mg/kg intravenously 3 times per week;
- Oral daily pyrazinamide, dosed on the basis of lean body weight: 1000 mg for patients weighing 40-55 kg, 1500 mg for those weighing 56-75 kg, or 2000 mg (maximum dose) for those weighing 76-90 kg;
- Ethionamide 15-20 mg/kg/day orally; initial dose of 250 mg/day, with titration every 1-2 days as tolerated to an average dose of 750 mg/day (maximum of 1 g/day in 3-4 divided doses); and
- Cycloserine 250 mg orally every 12 hours for 14 days, followed by 500-1000 mg/day, divided twice daily.
Potentially promising new agents for drug-resistant TB are being developed and have begun clinical testing. A new class is the bicyclic nitroimidazoles, which are prodrugs shown to be effective against both actively replicating and nonreplicating bacteria. The difficulty in the eradication of nonreplicating bacteria is the reason why current treatment involves prolonged duration in order to achieve cure and avoid relapse.
The active metabolite for the agent PA-824, des-nitroimidazole, has bactericidal activity against nonreplicating bacteria through the release of reactive nitrogen species, particularly nitric oxide. A phase 2 trial of 8 weeks of combination therapy with PA-824, moxifloxacin, and pyrazinamide has been designed but not yet initiated.
Patients receiving therapy for drug-resistant TB are at high risk for treatment failure owing to the use of second-line agents, which can be expensive, have significant adverse effect profiles, require a longer duration of treatment, are based on less rigorous data, and are less effective than first-line regimens for non-MDR-TB. With the aid of the WHO guidelines and drug susceptibilities, therapy should be patient-specific, with appropriate monitoring and patient education to achieve optimal response to therapy and minimize medication-related adverse effects.