Noninvasive ¹¹ C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis

Abstract

Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), and key TB antimicrobials, including rifampin, have restricted brain penetration. A lack of reliable data on intralesional drug biodistribution in infected tissues has limited pharmacokinetic (PK) modeling efforts to optimize TBM treatments. Current methods to measure intralesional drug distribution rely on tissue resection, which is difficult in humans and generally limited to a single time point even in animals. In this study, we developed a multidrug treatment model in rabbits with experi­ mentally induced TBM and performed serial noninvasive dynamic 11C-rifampin positron emission tomography (PET) over 6 weeks. Area under the curve brain/plasma ratios were calculated using PET and correlated with postmortem mass spectrometry. We demonstrate that rifampin penetration into infected brain lesions is limited, spa­ tially heterogeneous, and decreases rapidly as early as 2 weeks into treatment. Moreover, rifampin concentrations in the cerebrospinal fluid did not correlate well with those in the brain lesions. First-in-human 11C-rifampin PET performed in a patient with TBM confirmed these findings. PK modeling predicted that rifampin doses (≥30 mg/kg) were required to achieve adequate intralesional concentrations in young children with TBM. These data demonstrate the proof of concept of PET as a clinically translatable tool to noninvasively measure intralesional antimicrobial distribution in infected tissues.

Thalidomide and Phosphodiesterase 4 Inhibitors as Host Directed Therapeutics for Tuberculous Meningitis: Insights From the Rabbit Model

“…Results from this study revealed limited penetration of rifampin that diminished as early as 2 weeks post-treatment. PET scans also unveiled absence of antibiotics at the site of TB lesions (Tucker et al, 2018). Thus, a pediatric rabbit model of TBM infection provided a vital tool for our understanding of the effect of Mtb infection and disease progression on neuronal development, myelination, and microglia present in major white matter tracts, since these processes are very similar between rabbit and human brain development.…”

“…The penetration of antibiotics across the BBB during a multidrug treatment regimen was evaluated in the pediatric rabbit TBM model (Tucker et al, 2018). In this study, 4-8 days postnatal rabbits infected in the subarachnoid space with Mtb H37Rv were treated after 21 days of infection with a combination of 11 C rifampin, isoniazid, and rifampicin for 6 weeks, followed by PET imaging.…”

Treatment-Shortening Effect of a Novel Regimen Combining Clofazimine and High-Dose Rifapentine in Pathologically Distinct Mouse Models of Tuberculosis

“…Accordingly, we could not specifically evaluate the presence and distribution of caseous, necrotic lesions in the lungs at the start of treatment. Since disease in humans is heterogeneous and different pathological states can occur simultaneously in the same host, getting sufficient drug to these different lesions and understanding their activity within such lesions are essential for optimal antibacterial activity (27,36,54). Therefore, studies in animal models replicating these different pathologies are of interest during preclinical evaluations.…”

Treatment-shortening effect of a novel regimen combining high-dose rifapentine and clofazimine in pathologically distinct mouse models of tuberculosis

“…Accordingly, we could not specifically evaluate the presence and distribution of caseous, necrotic lesions in the lungs at the start of treatment. Since disease in humans is heterogeneous and different pathological states can occur simultaneously in the same host, getting sufficient drug to these different lesions and understanding their activity within such lesions is essential for optimal anti-bacterial activity (23, 32, 48). Therefore, studies in animal models replicating these different pathologies is of interest during preclinical evaluations.…”