The association between sterilizing activity and drug distribution into tuberculosis lesions

Abstract

Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a MALDI mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside1. In contrast, moxifloxacin which is active in vitro against persisters, a sub-population of Mycobacterium tuberculosis that persists in specific niches under drug pressure, and achieved treatment shortening in mice2, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We also suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration contributes to treatment outcome has wide implications for TB.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…[350][351][352] However, in C3HeB/FeJ mice that develop large caseous granulomas, clofazimine is less effective, perhaps because of the hypoxic conditions or reduced diffusion through caseous tissue, or both. 353,354 Clofazimine shows no bactericidal activity in patient sputum over the first 14 days of treatment. 355 However, in a phase 2 clinical trial, adding clofazimine at a dose of 100 mg daily for 21 months to multidrug background therapy (ie, the MDR tuberculosis treatment regimen) improved MDR tuberculosis treatment success versus placebo (74% vs 54%).…”

“…The concentrationtime profiles that M tuberculosis will be exposed to are defined by these barriers; these local profiles will either kill the M tuberculosis, amplify acquired drug resistance, or suppress acquired drug resistance. Antituberculosis drug penetration indices into the lung cavity, 434,435 193 showed that entry into the human tuberculosis cavity leads to a concentration gradient map, and they directly linked this gradient to the MICs (and hence resistance) in the different parts of the lung cavity for several antituberculosis drugs that patients were taking. 193 Studies are ongoing that aim to associate this drug penetration at the site of infection to more accessible drug concentrations in media such as the serum, to allow for better therapeutic drug monitoring.…”

“…‡Estimated from published graph of caseum-to-plasma ratio at steady state by Prideaux and colleagues. 434 §Pericardial fluid in tuberculosis pericarditis had pH 7·34 (thus pyrazinamide might not work), and a protein 61 g/L which would bind most rifampicin. The Lancet Respiratory Medicine Commission closer follow-up of adverse events, and frequent liver function tests.…”

The role of moxifloxacin in tuberculosis therapy

“…Mouse studies investigating potential treatment-shortening combinations found that the inclusion of pyrazinamide in the optimal combinations could result in even shorter treatment [59]. PRIDEAUX et al [60] used matrix-assisted laser desorption/ionization mass spectrometry imaging to show that rifampicin and pyrazinamide penetrate to the site of TB infection in lung, and there is evidence that rifampicin may accumulate in the caseum. Moxifloxacin, in contrast, was shown not to diffuse well into the caseum and this may explain the unexpectedly poor outcome due to relapses [9].…”

The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis

“…While this is known to constitute a mechanism of protection for the host, these bacterial niches have proven recalcitrant to treatment, as the fibrotic ring significantly reduces the penetration of antitubercular drugs (9,10). Further, these lesions undergo caseous necrosis, resulting in cavitation and dissemination of bacilli in the lungs to cause active disease (7,11).…”