[18F]F-TMP PET/CT Imaging for Bacterial Infections
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Pennsylvania
No Placebo Group
Trial Summary
What is the purpose of this trial?The purpose of this study is to study a radioactive tracer, a type of imaging drug that is injected into the body to see how it is taken up in sites of active infection using an imaging procedure called Positron Emission Tomography/Computed Tomography (PET/CT).
How is [18F]F-TMP PET/CT imaging different from other treatments for bacterial infections?
[18F]F-TMP PET/CT imaging is unique because it uses a PET scan with a special tracer based on the antibiotic trimethoprim to specifically detect live bacterial infections, distinguishing them from other conditions like inflammation or cancer. This method offers a more accurate way to identify bacterial infections without interference from other types of tissue changes.
4891112Is [18F]F-TMP PET/CT Imaging for Bacterial Infections safe for humans?
The research articles do not provide specific safety data for [18F]F-TMP PET/CT Imaging or its related compounds in humans.
123710What data supports the effectiveness of the drug [18F]Fluoropropyl-Trimethoprim for imaging bacterial infections?
Research shows that [18F]Fluoropropyl-Trimethoprim can effectively identify live bacterial infections, such as those caused by Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, with high specificity and low background noise in important tissues. This suggests it could be a useful tool for accurately detecting bacterial infections.
5691112Will I have to stop taking my current medications?
If you are taking the antibiotic trimethoprim, you will need to stop it at least 48 hours before the baseline PET/CT scan. For other medications, the trial protocol does not specify any requirements.
Eligibility Criteria
This trial is for adults with known or suspected bacterial infections who can give informed consent. It's not for pregnant or breastfeeding women, those who've taken trimethoprim within 48 hours, people unable to undergo imaging procedures, or anyone with severe conditions that could affect their safety in the study.Inclusion Criteria
I have or might have a bacterial infection, as indicated by tests or doctor's notes.
I am 18 years old or older.
Participant Groups
[18F]fluoropropyl-trimethoprim ([18F]F-TMP) is being tested as a radioactive tracer in PET/CT scans to see how it spreads and behaves in areas of the body with active bacterial infection.
2Treatment groups
Experimental Treatment
Group I: The Dynamic cohortExperimental Treatment1 Intervention
The Dynamic cohort will include up to 15 patients who will undergo approximately 60 minutes of dynamic scanning followed by up to 2 static skull base to mid-thigh (or feet if indicated) scans post injection of \[18F\]fluoropropyl-trimethoprim.
Group II: Biodistribution cohortExperimental Treatment1 Intervention
The Biodistribution cohort will include up to 5 patients who will undergo a series of vertex to mid-thigh (or feet if indicated) biodistribution \[18F\]fluoropropyl-trimethoprim PET/CT scans over a period of approximately 4 hours.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of PennsylvaniaPhiladelphia, PA
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Who is running the clinical trial?
University of PennsylvaniaLead Sponsor
References
Determination of trimethoprim and its oxidative metabolites in cell culture media and microsomal incubation mixtures by high-performance liquid chromatography. [2013]A high-performance liquid chromatographic method is presented for the determination of trimethoprim (TMP), 3'-hydroxy-TMP, 4'-hydroxy-TMP, alpha-hydroxy-TMP and two TMP N-oxides. The last two metabolites appear to decompose on liquid extraction. TMP and its oxidative metabolites are separated using a C18 radial-compression column and quantified by UV detection at 230 nm. Calibration curves are linear from 0.5 to at least 50 microM. The limit of detection is 0.05-0.15 micrograms/ml. In in vitro rat liver metabolism studies. 3'- and 4'-hydroxylation of TMP appear to be important metabolic pathways whereas TMP N-oxides are minor metabolites.
A comparative double-blind randomised study of single dose fosfomycin trometamol with trimethoprim in the treatment of urinary tract infections in general practice. [2022]A double-blind, double-dummy trial comparing a single dose treatment with fosfomycin trometamol (FT, 3 g) versus trimethoprim (TMP, 200 mg) was carried out in women with uncomplicated urinary tract infections. From 51 clinically evaluable patients, 44 were bacteriologically assessable at the 6-week follow-up. The results were as follows in the FT group (n = 22): eradication in 17 (77.3%); recurrence in 2 (9%); reinfection in 2 (9%), and persistence in 1 (4.5%). For the TMP group (n = 22) the results were: eradication in 12 (54.5%); recurrence in 1 (4.5%); reinfection in 1 (4.5%), and persistence in 8 (33.3%). There were no significant adverse events reported with either agent.
Trimethoprim: clinical use and pharmacokinetics. [2019]The recent marketing of trimethoprim (TMP) as a single drug has resulted in interest in the use of this drug to treat common infections. The history and antibacterial properties of TMP are reviewed. Indications for the clinical use of TMP are presented, and possible new uses for the drug are considered. The significance of adverse effects is discussed. The pharmacokinetic properties of TMP are reviewed with particular emphasis on the renal handling of the drug and its advantages over TMP/sulfonamide combinations in relation to renal function and toxicity.
In vitro and in vivo evaluation of [18F]ciprofloxacin for the imaging of bacterial infections with PET. [2019]The suitability of the 18F-labelled fluoroquinolone antibiotic ciprofloxacin ([18F]ciprofloxacin) for imaging of bacterial infections with positron emission tomography (PET) was assessed in vitro and in vivo.
Experimental studies on imaging of infected site with (99m)Tc-labeled ciprofloxacin in mice. [2013]Bacterial infection can pose a substantial diagnostic dilemma. (99m)Tc-labeled ciprofloxacin (CPF) was developed as a biologically active radiopharmaceutical to diagnose infection. In the present research, we studied the biodistribution and imaging properties of infection tracer (99m)Tc-CPF in a mouse model of infection.
Synthesis and biological evaluation of N-(2-[(18)F]Fluoropropionyl)-L-methionine for tumor imaging. [2016]N-position radiolabeled amino acids, such as N-(2-[(18)F]fluoropropionyl)-L-methionine ([(18)F]FPMET) as a derivative of L-methionine (MET), can potentially serve as a PET tracer for tumor imaging. In the current study, radiosynthesis and biological evaluation of [(18)F]FPMET as a new PET tumor agent are performed.
Design, synthesis, antibacterial activity and docking study of some new trimethoprim derivatives. [2017]In present study, nineteen novel trimethoprim (TMP) derivatives were designed, synthesized and evaluated for their antibacterial potential. Hydroxy trimethoprim 2 (HTMP) was synthesized by following the demethylation of 4-methoxy group at trimethoxy benzyl ring of TMP. Structure-activity relationship (SAR) studies were explored on HTMP by incorporating various substituents leading to the identification of some new compounds with improved antibacterial activities. The results revealed that the introduction of benzyloxy (4a-e) and phenyl ethanone (5a-e) group at 4-position of dimethoxy benzyl ring leads to overall increase in the antibacterial activity. The most potent antibacterial compound discovered is benzyloxy derivative 4b with MIC value of 5.0μM against Staphylococcus aureus and 4.0μM against Escherichia coli strains higher than the standard TMP (22.7μM against S. aureus and 55.1μM against E. coli). Substitution at 4-NH2 group was not tolerated and the resulting Schiff base derivatives 3a-h demonstrated very little or no antibacterial activity in the tested concentration domain. We further performed exploratory docking studies on dihydrofolate reductase (DHFR) to rationalize the in vitro biological data and to demonstrate the mechanism of antibacterial activity. For the ability to cross lipophilic outer membrane, logP was computed. It was found that the compounds possessing high hydrophobicity have high activity against E. coli.
Specific Imaging of Bacterial Infection Using 6″-18F-Fluoromaltotriose: A Second-Generation PET Tracer Targeting the Maltodextrin Transporter in Bacteria. [2018]6″-18F-fluoromaltotriose is a PET tracer that can potentially be used to image and localize most bacterial infections, much like 18F-FDG has been used to image and localize most cancers. However, unlike 18F-FDG, 6″-18F-fluoromaltotriose is not taken up by inflammatory lesions and appears to be specific to bacterial infections by targeting the maltodextrin transporter that is expressed in gram-positive and gram-negative strains of bacteria. Methods: 6″-18F-fluoromaltotriose was synthesized with high radiochemical purity and evaluated in several clinically relevant bacterial strains in cultures and in living mice. Results: 6″-18F-fluoromaltotriose was taken up in both gram-positive and gram-negative bacterial strains. 6″-18F-fluoromaltotriose was also able to detect Pseudomonas aeruginosa in a clinically relevant mouse model of wound infection. The utility of 6″-18F-fluoromaltotriose to help monitor antibiotic therapies was also evaluated in rats. Conclusion: 6″-18F-fluoromaltotriose is a promising new tracer that has significant diagnostic utility, with the potential to change the clinical management of patients with infectious diseases of bacterial origin.
Bacterial infection imaging with [18F]fluoropropyl-trimethoprim. [2019]There is often overlap in the diagnostic features of common pathologic processes such as infection, sterile inflammation, and cancer both clinically and using conventional imaging techniques. Here, we report the development of a positron emission tomography probe for live bacterial infection based on the small-molecule antibiotic trimethoprim (TMP). [18F]fluoropropyl-trimethoprim, or [18F]FPTMP, shows a greater than 100-fold increased uptake in vitro in live bacteria (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) relative to controls. In a rodent myositis model, [18F]FPTMP identified live bacterial infection without demonstrating confounding increased signal in the same animal from other etiologies including chemical inflammation (turpentine) and cancer (breast carcinoma). Additionally, the biodistribution of [18F]FPTMP in a nonhuman primate shows low background in many important tissues that may be sites of infection such as the lungs and soft tissues. These results suggest that [18F]FPTMP could be a broadly useful agent for the sensitive and specific imaging of bacterial infection with strong translational potential.
Halogenated trimethoprim derivatives as multidrug-resistant Staphylococcus aureus therapeutics. [2019]Incorporation of halogen atoms to drug molecule has been shown to improve its properties such as enhanced in membrane permeability and increased hydrophobic interactions to its target. To investigate the effect of halogen substitutions on the antibacterial activity of trimethoprim (TMP), we synthesized a series of halogen substituted TMP and tested for their antibacterial activities against global predominant methicillin resistant Staphylococcus aureus (MRSA) strains. Structure-activity relationship analysis suggested a trend in potency that correlated with the ability of the halogen atom to facilitate in hydrophobic interaction to saDHFR. The most potent derivative, iodinated trimethoprim (TMP-I), inhibited pathogenic bacterial growth with MIC as low as 1.25 μg/mL while the clinically used TMP derivative, diaveridine, showed resistance. Similar to TMP, synergistic studies indicated that TMP-I functioned synergistically with sulfamethoxazole. The simplicity in the synthesis from an inexpensive starting material, vanillin, highlighted the potential of TMP-I as antibacterial agent for MRSA infections.
Synthesis and evaluation of a [18F]formyl-Met-Leu-Phe derivative: A positron emission tomography imaging probe for bacterial infections. [2019]The tripeptide formyl-Met-Leu-Phe (fMLF) is a prototype of N-formylated chemotactic peptides for neutrophils owing to its ability to bind and activate the G protein-coupled formyl peptide receptor (FPR). Here, we developed an 18F-labeled fMLF derivative targeting FPR as a positron emission tomography (PET) imaging probe for bacterial infections. The study demonstrates that the fMLF derivative fMLFXYk(FB)k (X = Nle) has a high affinity for FPR (Ki = 0.62 ± 0.13 nM). The radiochemical yield and purity of [18F]fMLFXYk(FB)k were 16% and >96%, respectively. The in vivo biodistribution study showed that [18F]fMLFXYk(FB)k uptake was higher in the bacterial infected region than in the non-infected region. We observed considerably higher infection-to-muscle ratio of 4.6 at 60 min after [18F]fMLFXYk(FB)k injection. Furthermore, small-animal PET imaging studies suggested that [18F]fMLFXYk(FB)k uptake in the bacterial infected region was clearly visualized 60 min after injection.
Imaging sensitive and drug-resistant bacterial infection with [11C]-trimethoprim. [2022]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).