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 experimentally 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, spatially 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.
| Original language | English (US) |
|---|---|
| Article number | aau0965 |
| Journal | Science Translational Medicine |
| Volume | 10 |
| Issue number | 470 |
| DOIs | |
| State | Published - Dec 5 2018 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis. / Tucker, Elizabeth; Guglieri-Lopez, Beatriz; Ordonez Suarez, Alvaro; Ritchie, Brittaney; Klunk, Mariah H.; Sharma, Richa; Chang, Yong S.; Sanchez-Bautista, Julian; Frey, Sarah; Lodge, Martin; Rowe, Steven; Holt, Daniel; Gobburu, Jogarao V.S.; Peloquin, Charles A.; Mathews, William B; Dannals, Robert F; Pardo-Villamizar, Carlos A; Kannan, Sujatha; Ivaturi, Vijay D.; Jain, Sanjay.
In: Science Translational Medicine, Vol. 10, No. 470, aau0965, 05.12.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis
AU - Tucker, Elizabeth
AU - Guglieri-Lopez, Beatriz
AU - Ordonez Suarez, Alvaro
AU - Ritchie, Brittaney
AU - Klunk, Mariah H.
AU - Sharma, Richa
AU - Chang, Yong S.
AU - Sanchez-Bautista, Julian
AU - Frey, Sarah
AU - Lodge, Martin
AU - Rowe, Steven
AU - Holt, Daniel
AU - Gobburu, Jogarao V.S.
AU - Peloquin, Charles A.
AU - Mathews, William B
AU - Dannals, Robert F
AU - Pardo-Villamizar, Carlos A
AU - Kannan, Sujatha
AU - Ivaturi, Vijay D.
AU - Jain, Sanjay
PY - 2018/12/5
Y1 - 2018/12/5
N2 - 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 experimentally 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, spatially 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.
AB - 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 experimentally 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, spatially 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.
UR - http://www.scopus.com/inward/record.url?scp=85058108235&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058108235&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aau0965
DO - 10.1126/scitranslmed.aau0965
M3 - Article
C2 - 30518610
AN - SCOPUS:85058108235
VL - 10
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 470
M1 - aau0965
ER -