Why is long-term therapy required to cure tuberculosis?

Abstract

The authors argue that understanding and countering general bacterial mechanisms of phenotypic antibiotic resistance may hold the key to reducing the duration of treatment of all recalcitrant bacterial infections, including tuberculosis.

Figure 1. Duration of Curative Therapy for Pulmonary Tuberculosis Correlates Directly with Organism Burden

Pulmonary TB with a low bacterial burden (smear negative, culture negative [Cx-]; white bars) requires the shortest duration of four-drug therapy to achieve relapse rates <10%. Moderate burden (smear negative, culture positive [Cx+]; grey bars) patients require intermediate treatment courses, while high burden (smear positive, Cx+; black bars) cases require the longest duration of therapy. All patients were HIV negative and were treated with six months of therapy consisting of streptomycin (S), isoniazid (H), rifampin (R), and pyrazinamide (Z) during the intensive phase, followed by SHRZ or HR combinations in the continuation phase. Data for the figure were obtained from references [78–80,91–95].

Figure 2. Duration of Curative Therapy Is Longest for Disease States Associated with High-Organism Burden Lesions

(A) Active TB associated with cavitary lesions requires longest duration of therapy to cure. Treated pulmonary TB with open lesions and the highest bacterial burden (cavitary lesions with positive sputum cultures [Cx+] after two months of therapy; black bars) is associated with higher rates of relapse than are disease states associated with closed lesions (noncavitary, culture negative [Cx-] at two months; white bars, and noncavitary, Cx+ at two months; dark gray bars) or with lower bacterial burdens (noncavitary, Cx- at two months; white bars, or cavitary, Cx- at two months; light gray bars). All patients were HIV negative and received isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) or streptomycin (S) during the intensive phase followed by HR or H plus rifapentine (P) in the continuation phase. (B) Active disease states characterized by well-organized (HIV-) or poorly organized (HIV+) lesions require the same duration of therapy for cure. The relapse rate for high-burden (smear-positive) disease states associated with well-organized, cavitary lesions (HIV-; black bars) or loosely organized, noncaseating lesions (HIV+; white bars) treated with standard therapy (EHRZ for two months followed by HR for four months) is the same. Data for HIV+ and HIV- individuals were obtained from references [96,97].