A Sterilizing Tuberculosis Treatment Regimen Is Associated with Faster Clearance of Bacteria in Cavitary Lesions in Marmosets

Abstract

g Shortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treated Mycobacterium tuberculosis-infected marmosets with two drug regimens known to differ in their relapse rates in human clinical trials: the standard four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) that has very low relapse rates and the combination of isoniazid and streptomycin that is associated with higher relapse rates. As early as 2 weeks, the more sterilizing regimen significantly reduced the volume of lung disease by computed tomography (P ‫؍‬ 0.035) and also significantly reduced uptake of [18 F]-2-fluoro-2-deoxyglucose by positron emission tomography (P ‫؍‬ 0.049). After 6 weeks of therapy, both treatments caused similar reductions in granuloma bacterial load, but the more sterilizing, four-drug regimen caused greater reduction in bacterial load in cavitary lesions (P ‫؍‬ 0.009). These findings, combined with the association in humans between cavitary disease and relapse, suggest that the basis for improved sterilizing activity of the four-drug combination is both its faster disease volume resolution and its stronger sterilizing effect on cavitary lesions. Definitive data from relapse experiments are needed to support this observation.T reatment of drug-sensitive tuberculosis (TB) requires 6 months of chemotherapy with a combination of four agents, isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB), to achieve a durable cure (1). The durability of a regimen is determined by carefully measuring the rate of disease recrudescence over 1 to 2 years in patients after completing chemotherapy. Under controlled conditions in the setting of a clinical trial, the rate of relapse with active disease using this fourdrug combination is typically 2 to 4% (2), while under more typical conditions in national TB control programs, this rate can be as high as 10 to 14% (3, 4). Shortening the duration of treatment would greatly simplify the management of this disease by improving adherence, reducing the rate of adverse events, and reducing costs (5-7).An inverse relationship between the risk of relapse and the killing of bacilli in the sputum of patients (culture conversion after 2 months of treatment) has been proposed. Although some risk of relapse is clearly related to culture positivity at 2 months, this association appears to be dependent on geography and extent of disease (8). An additional risk factor for relapse observed in larger phase 3 clinical trials is the presence of cavitary lesions at the time of initial diagnosis of disease (9). However, a clinical trial to shorten therapy to 4 months for patients who did not have cavitary disease by chest X-ray and were culture negative at 2 months was stopped early because of unacceptably high rates ...

Prediction of Drug Penetration in Tuberculosis Lesions

“…Poor drug penetration can lead to subinhibitory concentrations of TB drugs and periods of local monotherapy, which in turn increase the risk of the emergence of resistant mutants. 2,6,7 In efficacy studies that focused on bacterial populations surviving drug treatment, the lesion compartments that failed to be sterilized at the end of therapy were mostly necrotic granulomas and caseous foci, 4,8–10 where hypoxic conditions reduce the activity of many drugs. Clinically, cavitary TB, where large numbers of bacilli are found in the cavity caseum, is associated with inferior cure rates and poor prognoses.…”

“…These bacteria are mostly extracellular, are slowly replicating or nonreplicating, and exhibit phenotypic drug tolerance as a result of hypometabolic adaptations. 4,9,10,16 …”

Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin α4β1–Expressing Immune Cells

“…Moreover, these endpoint assays cannot identify relevant changes that occur during lesional development and progression. The introduction of positron emission tomography and computed tomography (PET/CT) and [ 18 F]fluoro-2-deoxy-2-D-glucose ( 18 F-FDG)-based imaging has recently opened new avenues for investigating the pathogenesis of TB (11), especially in nonhuman primate-(5, 12–14) and rabbit-(15–17) based studies. Studies in macaques, a highly-translatable model of human TB, and have demonstrated that granulomas are independent within a single host and dynamic during infection (5, 10, 18) (and unpublished data).…”

Importance of Drug Pharmacokinetics at the Site of Action

“…Most patients with M. tuberculosis infection harbor ∼10 8 –10 9 organisms, with a variable proportion of these bacilli exhibiting preexisting, chromosomally mediated resistance to at least one drug of a typical multidrug regimen. To be effective, drugs in TB treatment regimens must penetrate into the sites of infection (including macrophages and liquefied contents of cavitary lesions), must be present at the site of disease in adequate concentrations to protect companion drugs from emergence of resistance, and should have activity against semidormant “persister” bacteria. Matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry imaging is now being used to characterize spatial distribution of candidate drugs into diseased lungs; early studies suggest that sterilizing (i.e., curative) activity of anti‐TB drugs appears to correlate with drug distribution into TB lesions .…”