| Autor: |
Lee IK; Department of Radiology and.; Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Jacome DA; Department of Radiology and., Cho JK; Department of Radiology and., Tu V; Department of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Young AJ; Department of Radiology and., Dominguez T; Department of Radiology and., Northrup JD; Department of Radiology and., Etersque JM; Department of Radiology and.; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Lee HS; Department of Radiology and., Ruff A; Department of Radiology and., Aklilu O; Department of Radiology and., Bittinger K; Department of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Glaser LJ; Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA., Dorgan D; Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and., Hadjiliadis D; Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and., Kohli RM; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Mach RH; Department of Radiology and., Mankoff DA; Department of Radiology and., Doot RK; Department of Radiology and., Sellmyer MA; Department of Radiology and.; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA. |
| Abstrakt: |
BACKGROUNDSeveral molecular imaging strategies can identify bacterial infections in humans. PET affords the potential for sensitive infection detection deep within the body. Among PET-based approaches, antibiotic-based radiotracers, which often target key bacterial-specific enzymes, have considerable promise. One question for antibiotic radiotracers is whether antimicrobial resistance (AMR) reduces specific accumulation within bacteria, diminishing the predictive value of the diagnostic test.METHODSUsing a PET radiotracer based on the antibiotic trimethoprim (TMP), [11C]-TMP, we performed in vitro uptake studies in susceptible and drug-resistant bacterial strains and whole-genome sequencing (WGS) in selected strains to identify TMP resistance mechanisms. Next, we queried the NCBI database of annotated bacterial genomes for WT and resistant dihydrofolate reductase (DHFR) genes. Finally, we initiated a first-in-human protocol of [11C]-TMP in patients infected with both TMP-sensitive and TMP-resistant organisms to demonstrate the clinical feasibility of the tool.RESULTSWe observed robust [11C]-TMP uptake in our panel of TMP-sensitive and -resistant bacteria, noting relatively variable and decreased uptake in a few strains of P. aeruginosa and E. coli. WGS showed that the vast majority of clinically relevant bacteria harbor a WT copy of DHFR, targetable by [11C]-TMP, and that despite the AMR, these strains should be "imageable." Clinical imaging of patients with [11C]-TMP demonstrated focal radiotracer uptake in areas of infectious lesions.CONCLUSIONThis work highlights an approach to imaging bacterial infection in patients, which could affect our understanding of bacterial pathogenesis as well as our ability to better diagnose infections and monitor response to therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT03424525.FUNDINGInstitute for Translational Medicine and Therapeutics, Burroughs Wellcome Fund, NIH Office of the Director Early Independence Award (DP5-OD26386), and University of Pennsylvania NIH T32 Radiology Research Training Grant (5T32EB004311-12). |
