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Staphylococcus aureus infections are a major threat in healthcare, requiring adequate early-stage diagnosis and treatment. This calls for novel diagnostic tools that allow noninvasive in vivo detection of staphylococci. Here we performed a preclinical study to investigate a novel fully-human monoclonal antibody 1D9 that specifically targets the immunodominant staphylococcal antigen A (IsaA). We show that 1D9 binds invariantly to S. aureus cells and may further target other staphylococcal species. Importantly, using a human post-mortem implant model and an in vivo murine skin infection model, preclinical feasibility was demonstrated for 1D9 labeled with the near-infrared fluorophore IRDye800CW to be applied for direct optical imaging of in vivo S. aureus infections. Additionally, 89Zirconium-labeled 1D9 could be used for positron emission tomography imaging of an in vivo S. aureus thigh infection model. Our findings pave the way towards clinical implementation of targeted imaging of staphylococcal infections using the human monoclonal antibody 1D9.

Staphylococcus aureus infections are a major threat in healthcare, requiring adequate early-stage diagnosis and treatment. This calls for novel diagnostic tools that allow noninvasive in vivo detection of staphylococci. Here we performed a preclinical study to investigate a novel fully-human monoclonal antibody 1D9 that specifically targets the immunodominant staphylococcal antigen A (IsaA). We show that 1D9 binds invariantly to S. aureus cells and may further target other staphylococcal species. Importantly, using a human post-mortem implant model and an in vivo murine skin infection model, preclinical feasibility was demonstrated for 1D9 labeled with the near-infrared fluorophore IRDye800CW to be applied for direct optical imaging of in vivo S. aureus infections. Additionally, 89Zirconium-labeled 1D9 could be used for positron emission tomography imaging of an in vivo S. aureus thigh infection model. Our findings pave the way towards clinical implementation of targeted imaging of staphylococcal infections using the human monoclonal antibody 1D9.

Despite major advances in medicine and patient care, infections remain a great threat to human health. This is exacerbated by increasing rates of surgical interventions and the rapid increment of antimicrobial resistance that poses challenges for effective therapeutic interventions. Current diagnostic tools for infection detection, such as molecular and culturing techniques, are time-consuming and rely on the collection of clinical samples which is not always possible. Furthermore, there is a great need for improvement of the diagnosis and treatment of infections at early stages. In this context, imaging is an attractive approach to localize sites of infection. However, traditional imaging modalities, such as radiography, are non-specific and unable to distinguish infection from sterile inflammation. To solve this specificity challenge, targeted molecular imaging, based on the use of specific tracers, has emerged. This approach enables specific, non-invasive and real-time visualization of causative pathogens. Accordingly, the aim of the research described in this PhD thesis was to develop novel tracers for targeted fluorescence imaging of infections, and to evaluate optical fluorescence imaging for the detection of infections at early stages. To achieve these objectives, the evaluation of novel fluorescent tracers was performed through in vitro, ex vivo and in vivo analyses following various clinical settings, such as fluorescence-guided arthroscopy or fluorescence-guided bronchoscopy. The results demonstrate the potential of targeted fluorescence imaging for early detection of Gram-positive bacterial and fungal infections, and highlight the importance of targeted imaging to accelerate the time-to-result between diagnosis and treatment, which is crucial for successful infection management.

Bacteriële infecties vormen een veelvoorkomende en grote bedreiging voor de gezondheid van de mens. Ze zijn verantwoordelijk voor ernstige morbiditeit en mortaliteit onder patiënten. De definitieve diagnose van infectie kan alleen worden verkregen via microbiologische kweken en moleculaire detectietechnieken, wat vaak tijdrovend is. Bovendien is het soms niet mogelijk om geschikte biopten of kweekmateriaal te verkrijgen, waardoor het stellen van de juiste diagnose zeer uitdagend kan zijn. Deze problemen kunnen mogelijk omzeild worden met behulp van bacterie-specifieke beeldvormingstechnieken. Helaas zijn de huidige beeldvormende technieken om infectieziekten te diagnosticeren niet in staat om een bacteriële infectie te onderscheiden van een steriele ontsteking. Nieuwe beeldvormende technieken zijn daarom dringend nodig voor een snelle, nauwkeurige en bij voorkeur real-time diagnose van bacteriële infecties. Dit proefschrift beschrijft de ontwikkeling van nieuwe bacterie-gerichte beeldvormingstechnieken met een focus op het gebruik van fluorescente moleculen die specifiek aan bacteriën binden. De resultaten laten zien dat fluorescente beeldvorming van bacteriële infecties geschikt is voor toepassing op geëxplanteerde materialen, tijdens artroscopie of bronchoscopie, of intra-operatief. Samenvattend kan geconcludeerd worden dat bacterie-gerichte beeldvormingstechnieken goed toepasbaar zijn voor een snellere diagnose van bacteriële infecties., Bacterial infections occur frequently and are a major threat to human health, causing high morbidity and mortality all over the world. For adequate treatment of infections, a rapid and precise diagnosis is imperative. Presently, this is achieved via microbiological culture and molecular detection, which are often time-consuming processes. Moreover, it is not always possible to obtain appropriate material for culturing, which complicates the diagnostic process. Therefore, the PhD research described in this thesis was aimed at exploring imaging-based techniques for faster and preferably real-time diagnosis of infectious diseases, and for rapid distinction of bacterial infection from sterile inflammation. To this end, the development of new bacteria-targeted imaging modalities was reviewed with a special focus on bacteria-targeted imaging with fluorescent tracers. Subsequently, the possible use of different tracers for infection imaging was experimentally explored. The results show that imaging with fluorescent bacteria-targeted tracers can be readily applied to detect infection ex vivo, by arthroscopy or bronchoscopy, or intra-operatively. Altogether, it is concluded that bacteria-targeted fluorescence imaging approaches may allow faster, real-time diagnosis of bacterial infections.