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Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality. We have developed new methods to synthesize 18 F-pretomanid (chemically identical to the antibiotic) and performed cross-species positron emission tomography (PET) imaging to noninvasively measure pretomanid concentration-time profiles. Dynamic PET in mouse and rabbit models of TB meningitis demonstrates excellent CNS penetration of pretomanid but cerebrospinal fluid (CSF) levels does not correlate with those in the brain parenchyma. The bactericidal activity of the BPaL regimen in the mouse model of TB meningitis is substantially inferior to the standard TB regimen, likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Finally, first-in-human dynamic 18 F-pretomanid PET in six healthy volunteers demonstrates excellent CNS penetration of pretomanid, with significantly higher levels in the brain parenchyma than in CSF. These data have important implications for developing new antibiotic treatments for TB meningitis. Pretomanid has been approved for use in cases of multi-drug resistant pulmonary tuberculosis, yet the penetration of this antibiotic into other target tissues is not well established. Authors provide insight on pretomanid pharmacokinetics in the central nervous system, using positron emission tomography in animal models, and human studies.

Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we perform first-in-human dynamic 18 F-pretomanid positron emission tomography (PET) in eight human subjects to visualize 18 F-pretomanid biodistribution as concentration-time exposures in multiple compartments (NCT05609552), demonstrating preferential brain versus lung tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of several antibiotics, active against multidrug resistant (MDR) Mycobacterium tuberculosis  strains, are confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicts human dosing necessary to attain therapeutic brain exposures. These data are used to design optimized, pretomanid-based regimens which are evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrate discordant activities in brain and lung tissues in the same animal, correlating with tissue antibiotic exposures. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for developing treatments for meningitis and other infections in compartments with unique antibiotic penetration. Antibiotic treatments for tuberculous meningitis, the deadliest form of tuberculosis, are not optimized. Here, PET in human and animal studies is used to measure the biodistribution of several antibiotics to develop optimized regimens for drug-resistant tuberculous meningitis.

Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.

Invasive mold infections are a major cause of mortality in immunosuppressed and cancer patients. Diagnosis is challenging, requiring invasive procedures or reliance on fungal biomarkers with limited sensitivity and an inability to detect non-Aspergillus molds. Here, we perform whole-body 18 F-fluorodeoxysorbitol ( 18 F-FDS) positron emission tomography (PET) in nine prospectively enrolled patients with high-suspicion of invasive mold infections (eventually confirmed using culture or molecular assays, n = 4) or other pathologies (n = 5) with localization of 18 F-FDS PET signal to infection sites as the primary outcome (NCT05611892). 18 F-FDS PET (120 or 180 min after injection), rapidly detects and localizes invasive pulmonary and cerebral infections due to Aspergillus , non- Aspergillus (galactomannan-negative), or azole-resistant molds, and differentiates them from sterile inflammation or cancer. Moreover, 18 F-FDS selectively and rapidly accumulates intracellularly in a range of clinically relevant molds, including azole-resistant molds, via a saturable process. In animals, 18 F-FDS PET is able to detect and localize pulmonary and cerebral aspergillosis, as well as rhinosinusal infections due to Aspergillus , Rhizopus , and Mucor , confirming the clinical data. 18 F-FDS can be easily synthesized from 18 F-fluorodeoxyglucose ( 18 F-FDG), which is widely available, and represents a promising, noninvasive diagnostic tool for detecting, localizing and monitoring of invasive mold infections throughout the body. In this study, the authors describe an imaging technology, 18 F-FDS PET, for noninvasive detection, localization and monitoring of invasive mold infections, including Aspergillus , non- Aspergillus and azole-resistant molds, throughout the body.

Molecular imaging is an emerging technology that enables the noninvasive visualization, characterization, and quantification of molecular events within living subjects. Positron emission tomography (PET) is a clinically available molecular imaging tool with significant potential to study pathogenesis of infections in humans. Molecular imaging is an emerging technology that enables the noninvasive visualization, characterization, and quantification of molecular events within living subjects. Positron emission tomography (PET) is a clinically available molecular imaging tool with significant potential to study pathogenesis of infections in humans. PET enables dynamic assessment of infectious processes within the same subject with high temporal and spatial resolution and obviates the need for invasive tissue sampling, which is difficult in patients and generally limited to a single time point, even in animal models. This review presents current state-of-the-art concepts on the application of molecular imaging for infectious diseases and details how PET imaging can facilitate novel insights into infectious processes, ongoing development of pathogen-specific imaging, and simultaneous in situ measurements of intralesional antimicrobial pharmacokinetics in multiple compartments, including privileged sites. Finally, the potential clinical applications of this promising technology are also discussed.

Central nervous system (CNS) tuberculosis (TB) is the most severe form of extra-pulmonary TB and disproportionately affects young children where the developing brain has a unique host response. New Zealand white rabbits were infected with Mycobacterium tuberculosis via subarachnoid inoculation at postnatal day 4-8 and evaluated until 4-6 weeks post-infection. Control and infected rabbit kits were assessed for the development of neurological deficits, bacterial burden, and postmortem microbiologic and pathologic changes. The presence of meningitis and tuberculomas was demonstrated histologically and by in vivo magnetic resonance imaging (MRI). The extent of microglial activation was quantified by in vitro immunohistochemistry as well as non-invasive in vivo imaging of activated microglia/macrophages with positron emission tomography (PET). Subarachnoid infection induced characteristic leptomeningeal and perivascular inflammation and TB lesions with central necrosis, a cellular rim and numerous bacilli on pathologic examination. Meningeal and rim enhancement was visible on MRI. An intense microglial activation was noted in M. tuberculosis-infected animals in the white matter and around the TB lesions, as evidenced by a significant increase in uptake of the tracer 124I-DPA-713, which is specific for activated microglia/macrophages, and confirmed by quantification of Iba-1 immunohistochemistry. Neurobehavioral analyses demonstrated signs similar to those noted in children with delayed maturation and development of neurological deficits resulting in significantly worse composite behavior scores in M. tuberculosis-infected animals. We have established a rabbit model that mimics features of TB meningitis in young children. This model could provide a platform for evaluating novel therapies, including host-directed therapies, against TB meningitis relevant to a young child's developing brain.

Little is known of pediatric clinicians’ experiences with and approaches to taking care of immigrant children who have been in US custody. The objectives of this article are to (1) recognize the challenges facing pediatric clinicians in caring for immigrant children previously in custody, and (2) propose ways that healthcare and legal professionals can collaborate to optimize the wellbeing of formerly detained immigrant children. We identify themes by assessing answers to multiple choice and short responses from a national survey. These findings can help to identify current issues faced by both detained immigrant children and pediatric clinicians, and suggest approaches to addressing these issues.

Tools for noninvasive detection of bacterial pathogens are needed but are not currently available for clinical use. We have previously shown that para-aminobenzoic acid (PABA) rapidly accumulates in a wide range of pathogenic bacteria, motivating the development of related PET radiotracers. In this study, 11C-PABA PET imaging was used to accurately detect and monitor infections due to pyogenic bacteria in multiple clinically relevant animal models. 11C-PABA PET imaging selectively detected infections in muscle, intervertebral discs, and methicillin-resistant Staphylococcus aureus-infected orthopedic implants. In what we believe to be first-in-human studies in healthy participants, 11C-PABA was safe, well-tolerated, and had a favorable biodistribution, with low background activity in the lungs, muscles, and brain. 11C-PABA has the potential for clinical translation to detect and localize a broad range of bacteria.

Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure 1 . However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments 2 . In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration–time profiles in humans 3 . Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study 4 using dynamic [ 11 C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [ 11 C]rifampin PET–CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET–CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET–CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration–time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development. Distinct patterns of exposure to a first-line tuberculosis drug in separate lung lesions within patients are revealed by PET–CT imaging. Use of the technique might help optimize the duration and dosing of antimicrobial drugs.

Tuberculous meningitis is a serious, life-threatening disease affecting vulnerable populations, including HIV-infected individuals and young children. The US National Institutes of Health convened a workshop to identify knowledge gaps in the molecular and immunopathogenic mechanisms of tuberculous meningitis and to develop a roadmap for basic and translational research that could guide clinical studies.