Tuberculosis is often a difficult infection to treat. A new review article summarizes the many manifestations of the disease and the major treatment options in the various contexts in which the disease occurs.
Tuberculosis, a scourge since prehistoric times, affects more than 9 million people and causes death in 1.5 million people each year. Effective treatment has been available for 60 years, but generally takes 6 months, and resistance to the drugs, which is increasing throughout the world, threatens the effectiveness of treatment.
• What is the standard regimen for drug-susceptible tuberculosis?
The standard treatment regimen for presumably drug-susceptible tuberculosis includes an induction phase consisting of rifampin, isoniazid, and pyrazinamide, to which ethambutol is added as protection against unrecognized resistance to one of the three core drugs. Once susceptibility to isoniazid, rifampin, and pyrazinamide has been confirmed, ethambutol can be discontinued. The induction phase is followed by a consolidation phase consisting of rifampin and isoniazid for an additional 4 months of treatment.
• What challenges are associated with the relatively lengthy course of treatment for tuberculosis?
The standard 6-month treatment regimen for drug-susceptible tuberculosis is an exceptionally long course of treatment as compared with the duration of treatment of other bacterial infectious diseases. The prolonged regimen poses two major challenges to success: managing drug toxicity and ensuring that patients adhere to the full course of treatment. Drug toxicity is substantial; a review of retrospective studies using similar definitions estimates that 3 to 13% of patients have hepatotoxic effects. A recent prospective cohort study of patients with drug-susceptible disease who received standard tuberculosis therapy documented a 15% incidence of adverse drug reactions resulting in interruption or discontinuation of one or more of the drugs. Of these adverse reactions, 7.7% resulted in hospitalization, disability, or death. A wide variety of reactions were reported; the most common were hepatotoxic effects, gastrointestinal disorders, allergic reactions, and arthralgias. Overall, 16 to 49% of patients do not complete the regimen. Reasons for failure to complete treatment are varied and include adverse drug reactions, cost of treatment, stigma, and the patient’s belief that cure has been achieved when symptoms have resolved and bacteria can no longer be recovered from the sputum. Treatment support and direct-observation programs are useful in improving adherence but have not entirely overcome these factors.
Morning Report Questions
Q: What factors might explain the poor response of some patients to antimycobacterial therapy?
A: Recent studies suggest that in many patients, Mycobacterium tuberculosis bacteria are sequestered in compartments that are inaccessible to antibiotic action; this could explain the poor long-term treatment response in some patients despite clearance of bacteria from the sputum. The leading candidates for these sequestered compartments are the interior of granulomas, abscesses, and cavities. Another potential explanation for the poor clinical responses in some patients is inadequate serum antimycobacterial drug levels, since low serum levels further impede the ability of drugs to penetrate infectious foci. One cause of low serum levels can be inadequate absorption. Isoniazid, rifampin, and pyrazinamide levels are decreased when the drug is taken with food, whereas rifapentine absorption is increased with a high-fat meal; fluoroquinolone absorption is decreased by antacids. Genetically determined metabolic pathways can also influence serum drug levels. N-acetyltransferase is an enzyme that is involved in isoniazid clearance; human genetic variation in the gene encoding N-acetyltransferase (NAT2) can lead to underexposure (in “fast acetylators”) or to an elevated risk of hepatotoxicity (in “slow acetylators”); this slow-acetylator genotype is present in more than 50% of white populations.
Q: What new antimycobacterial drugs are on the horizon?
A: Several new classes of antimycobacterial drugs have been developed in the past 15 years. Two of these agents, the diarylquinoline bedaquiline and the nitroimidazooxazole delamanid, have received accelerated regulatory approval and are currently being confirmed in phase 3 clinical trials. It is hoped that such agents will lead to shorter and more effective regimens for the treatment of multidrug-resistant tuberculosis and will allow clinicians to avoid the use of injectable agents, which have unacceptably high rates of ototoxicity and renal toxicity. At the present time, the role of the new agents in the treatment of drug-susceptible tuberculosis appears to be limited. Other new drug classes (benzothiazinones and imidazopyridines) show promise in preclinical studies but have not yet progressed to clinical trials.