While cancer itself may impair individuals' immunity, cancer treatments like chemotherapy, radiotherapy as well as immunosppressive treatments like bone marrow stem cell transplants and targeted biological drugs can significantly impair immunity and render individuals prone to microbial infection. For example, people with cancer can suffer from severe leucopenia, where the white blood cell count becomes very low due to radiation or chemotherapy treatment (32). Consequently, this lowers the natural immunity to fight against a range of infections, in particular bacterial and fungal pathogens. These infections may be mild, or severe enough to be life threatening, for example, mild skin infection or a fatal fungal pneumonia. Patients with life-threatening blood cancers (e.g., acute leukemia/high grade lymphoma or advanced myeloma) may require more aggressive chemotherapeutic treatment, resulting in greater risk of developing fungal infections (33). Moreover, novel targeted drugs and biological immunotherapies including CAR-T (Chimeric antigen re-engineered T cells) are changing the risk profile for developing serious opportunistic infections. Significant challenges remain in terms of early detection, management, and monitoring success of therapeutic interventions for these infections.

In terms of fungal risk following treatment related immunosuppression, patients with haematological malignancies mostly suffer from invasive aspergillosis (primarily caused by A. fumigatus) and some develop invasive candidiasis (mainly caused by C. albicans). Invasive aspergillosis in high-risk immunocompromised patients has an attributable mortality of 27%–72% making it a leading cause of death in this group of patients (34). Invasive candidiasis is one of the most common blood stream infections in Intensive Care Units (ICUs) and the associated mortality rate is 20%–30% (35). Less common Candida species like C. parapsolosis and C. glabrata are contributing to an increasing proportion of infections, with rising rates of azole (a commonly used class of antifungal agent) resistance (36). These IFI remain difficult to diagnose in a timely fashion, as there is no universally available “gold standard” test. Routine microbiological tests with fungal culture often do not yield positive isolates or lead to false negative results and thus may fail to determine the overall burden of the disease. Diagnosis based on fungal biomarkers including beta-D-glucan and galactomannan, which lack specificity, combined with radiological features and histological changes (EORTC-MSG criteria) are helpful but imprecise (37, 38). They may still underestimate the incidence of IFI, specifically with use of newer antifungal prophylaxis regimens that reduce the diagnostic sensitivity and specificities of these methods.

Audits in UK hemato-oncology units have shown an incidence of proven IFI of 6.5%–21%, while up to 50% of patients get treated with empirical antifungals during febrile neutropenia episodes (39). Thus, many of these patients may still receive antifungal treatment despite no IFI due to poor diagnostic tools, and this potential overuse of antifungals may lead to serious consequences for individual patients and potentially drive antifungal resistance. In addition, it has an economic impact on healthcare systems. The National Health Service of England's antifungal budget is approximately £150M and is increasing year on year, with the majority (£87M) spent in haemato-oncology units (39). Globally, antifungal resistance is spreading rapidly, including the emergence of new Multidrug Resistant (MDR) fungal pathogens associated with increased mortality. Additionally, reports of increasing azole-resistant infections caused by A. fumigatus—the commonest cause of invasive aspergillosis in the UK, and rapid spread of the MDR organism, C. auris, are of significant clinical concern (40, 41). Improvement requires early sensitive and specific detection of fungal infections with effective noninvasive diagnostic tools for IFI, which remains an unmet need.

Prosthetic vascular tube grafts (placed at open surgery) and endovascular stents or endografts are increasingly used to treat life-threatening arterial aneurysms, dissection, and occlusive vascular disease (42). Vascular Graft Infection (VGI) is estimated to complicate 0.5%–6% implanted grafts depending on the anatomical location of the implant, causing significant morbidity, mortality, and economic burden (43, 44). Vascular implant infection is more common when the device has been used to treat infective pathology of the blood vessel itself, for example a mycotic aneurysm. Depending on the location of the graft, up to 70% mortality with VGI is reported, and graft infections in the lower limbs frequently lead to amputation. No arterial graft is designed to ever be removed, and doing so mandates major surgery to remove the graft and then reconstruct the blood supply to downstream tissues (45). The economic burden associated with VGI is £541M per year in the United States alone (46). These costs may increase due to the widespread use of aortic endografts in elderly and co-morbid patients, in whom infection is more common. The morbidity associated with other vascular implants such as intravenous access devices, pacemakers and internal cardiac defibrillators remains a major clinical challenge since treatment options are poor. The current focus remains on prevention (47, 48).

A very wide range of organisms are implicated in vascular infection, and the most common organisms tend to vary by the site of the implant and the presence of an associated graft-enteric or graft-respiratory tract fistula. The most frequently isolated bacteria are S. aureus (30%) and S. epidermidis (17%) (49). Although less common, graft infections due to Gram-negative bacteria have increased in frequency. Enterococcus faecalis is the predominant pathogen in cases of aorto-enteric fistulae (50). While acute infections occur within four months following the surgery and are associated with virulent bacteria, late/chronic infections can occur many years of surgery, for example following a bacteremia. The causative agents of mycotic aneurysms vary by geographical location, for example salmonella infection is more common in Asia. The diagnosis of VGI is well-recognized to be challenging, and again as there is no “gold standard test” for the condition, it is instead defined by syndromic criteria (47, 51). Laboratory findings may be helpful (raised inflammatory markers, and positive blood cultures), but are neither sensitive nor specific. Current clinically available imaging techniques usually provide non-specific information and cannot identify causative pathogens (beyond the identification of visceral fistulae, indicating likely polymicrobial infection). As almost all patients are already receiving antimicrobial treatment at the time of surgical removal of the implant, microbiological identification is difficult as bacterial cultures often remain negative, rendering targeted treatment impossible unless an organism is identifiable by non-culture based techniques (e.g., PCR) (52). Use of 18FDG is limited by the tendency of prosthetic implants to drive a sterile inflammatory reaction (53), which can be hard to differentiate from low-grade inflammation caused by infection. It is notable that many decades after the identification of mycotic aneurysms as a pathological entity, there remains no accepted consensus diagnostic criteria, and the imaging features remain woefully non-specific. The problem is complicated by the identification of bacteria in approximately one third of aneurysms that would otherwise not be considered “mycotic”, in mural thrombus, and in atheromatous plaque (54, 55). The ability to diagnose the presence of pathogens within the blood vessel wall, or within atheroma, would represent a major clinical advance (56).

Immunosuppressive drugs play a major role in the prevalence of infections after transplantation of solid organs (kidney, liver, heart, intestine, and lung), which may lead to the recipient's death within the first year of transplantation (57, 58). A Swiss Transplant Cohort Study (SOTS) between 2008 and 2014 with ≥12 months of follow-up, revealed 55% patients developing >3,500 infection episodes during their first-year post transplantation (59). Among these infections, bacterial infections were most prevalent (63%), predominantly Gram-negative Enterobacteriace in heart, lung, kidney and liver transplant recipients, specifically P. aeruginosa and Gram-positive Enterococcus spp. About 30% were viral infections associated with kidney, liver and heart transplant recipients. Although fungal infections were least common (∼7.5%), Candida spp. was mostly prevalent (60%) in liver transplant patients, while A. fumigatus (1.4%) infection was lowest in all solid organ transplant recipients. The diagnostic uncertainty and delays in diagnosis remains a challenge in these immunocompromised patients, often leading to graft rejection and high mortality risk.

With the advancement of medical science and technology, patients are often treated with temporary or permanent implantable devices including dental, cardiac, orthopedic implants and prostheses. These devices pose a risk of becoming infected, especially in immunocompromised patients or those with other underlying health conditions. According to the United States Centre for Disease Control (CDC), 50%–70% of the 2 million healthcare-associated or nosocomial infections could be attributed to implanted medical devices (44). As expected, infections in all intravascular medical devices (including VGI) including cardiac pacemakers, mechanical heart valves, and ventricular assist devices, are identified as life-threatening (60). A high risk of mortality (>25%) is associated with prosthetic valve endocarditis (61). Ventilator-associated pneumonia in intubated patients is one of the most common infections in the ICU (62). The most common bacteria found in intravascular devices and prosthetic joints are coagulase-negative staphylococci (CoNS) (e.g., S. epidermidis), then S. aureus, and less common pathogens include Enterococcus spp., Candida spp., E. coli and Klebsiella species (63). Conversely, E. coli, Candida spp., and Enterococcus spp. are the most common in urinary catheter related infections (64). Along with nosocomial pathogens, opportunistic microorganisms from the host's respiratory, urinary, and gastrointestinal tract can also colonize the implanted device.

Outside of cancer, those with diabetes, cirrhotic liver disease, receiving steroid therapy or living with untreated HIV, cystic fibrosis (CF), chronic granulomatous disease as well as those treated for severe COVID-19 disease, are among the most significant groups of immunocompromised patients, who are at high risk of serious microbial infections.

Pulmonary infections are a major cause of morbidity and mortality in people living with untreated HIV, including with Strep. pneumoniae, in particular due to Pneumocystis spp., and Mycobacterium tuberculosis (TB). Worldwide, roughly one third of people living with HIV/AIDS become co-infected with TB (65). In 2015, there were 1.14 million new cases of tuberculosis in people with HIV/AIDS, of which 400,000 people died as a direct result of TB (66). Death due to TB is more common in low- and middle-income countries, in particular Africa, which has higher rates of MDR TB (66). Patients with untreated HIV have a greater risk of progression from latent to active TB, with an associated increased risk of onward nosocomial TB transmission. In addition, people living with untreated HIV are susceptible to a myriad of fungal infections, including cryptococcal disease, mucocutaneous candidiasis, and aspergillosis (67).

CF, one of the most common lethal genetic disorders in Caucasians, affects over 60,000 patients globally (68). Patients living with CF commonly develop pulmonary infections with P. aeruginosa. Other microorganisms include S. aureus, M. abscessus, Burkholderia cepacia, and A. fumigatus. Emerging MDR P. aeruginosa and S. aureus infection in CF patients are a growing concern, and preclude these patients from consideration of lung transplantation (69, 70).

The recent COVID-19 pandemic also revealed the co-morbidity and co-mortality in patients from bacterial or fungal infection in those with severe SARS-CoV-2 infection (71). Most reported fungal infections in COVID-19 patients include aspergillosis, candidiasis, and mucormycosis. The main causative agent for mucormycosis is Mucorales spp., often incorrectly called a “black fungus infection” (72). Fungal infections resistant to antifungal treatment have also been described in patients with severe COVID-19 (73), but diagnostic uncertainties remain with lack of specific and sensitive biomarkers or imaging tools.

Similarly, causative agents for FUO (74), osteomyelitis and septic arthritis (75) as well as deep soft tissue and deep wound infections (76) are sometimes difficult to confirm, and so empirical therapy is often used. Table 1 summarizes the pathogens requiring particularly urgent development of specific infection imaging diagnostics.

The potential arsenal of radionuclides (both metal and non-metal) in nuclear medicine is rich, and both PET and SPECT imaging radiometals are available for evaluating organ function, detecting cancer, measuring blood flow, and investigating metabolic processes. The major advantage of using nuclear medicine over other imaging techniques is to achieve detailed functional and anatomical (combined with CT/MRI) changes through the administration of radioactive compounds to patients, in very low dose (nanomolar or less) which is otherwise difficult to obtain. An ideal radiometal to be used in nuclear medicine must fulfil the first requirement of coordinated complex stability, both during radiolabeling and in the in vivo system. This stability can be achieved by binding the radiometal with a ligand or chelator. The type of chelator used depends on the chemistry and application of the radiometals. This stable metal-ligand complex can then be administered in vivo, and PET/SPECT scanners can image the accumulation in different organs in the body. BFCs can complex metals and can be conjugated with targeting moieties (Figure 2A). This exerts specificity of the radiotracer for a particular disease diagnosis and possible treatment (theranostics). Therefore, the selection of radiometals and the design of BFCs are critical to develop diagnostics for any specific disease condition. Of note, a single BFC, which can accommodate different radiometals and biomolecules, would be preferable. Available radiometals and chelators currently used in nuclear medicine are summarized in Table 2. Figure 2B shows the structure of the most commonly used BFCs in nuclear medicine (77). Details of radiometals and their chelator chemistry have been discussed elsewhere (78, 79).

For imaging infection diagnostics, radiometals should meet some additional criteria: (a)

SPECT/PET imaging modality compatibility (preferably PET imaging as PET is easier to quantify than SPECT).

Development of diagnostics relies on careful exploration of differential biochemistry of the infective pathogen and its host. The current strategies to design infection-specific diagnostics are based on targeting microbial metabolic pathways or microbial cellular components, using antimicrobial peptides and antibiotics, and targeting essential or transitional metals for pathogens. Figure 4(A), 4(B) depicts the diagnostic developments specifically in bacterial and fungal cells, respectively.

Radiolabeled siderophores have been investigated since the early 1980s (170). [¹¹¹In]In-DFO-B has been proposed for abscess detection. Studies were carried out in rabbits with turpentine-induced abscess and Staphylococcus-induced abscess. Images at 4 h and 24 h show the abscess clearly visible (171).

Over the years, gallium compounds have been particularly important in the development of radiopharmaceuticals (172). The chemical and biological similarities between Gallium(III) (Ga³⁺) and Iron(III) (Fe³⁺) are key to the use of Ga³⁺ (radioisotopes) in many applications (173). Non-radioactive gallium compounds were also investigated for cancer diagnostics (174). The similarity between Ga³⁺ to Fe³⁺ enables radioactive gallium (^68/67Ga) bound to siderophores as BFCs for investigating many biological applications (Supplementary Table S1).

For infection imaging purposes, a ⁶⁷Ga-labeled analogue of ferrichrome has shown in vitro uptake in the fungus Ustilago sphaerogena via an active mechanism that was indistinguishable from non-radiolabeled ferrichrome (175). Recent preclinical studies have been exploring a range of siderophores to develop ⁶⁸Ga-labeled-siderophore based PET tracers for bacterial and fungal infection.

In vitro evaluation of siderophores mainly targeting A. fumigatus has been conducted (176). [⁶⁸Ga]Ga-desferri-ferricrocin ([⁶⁸Ga]Ga-FC) and [⁶⁸Ga]Ga-desferri-triacetylfusarinine C ([⁶⁸Ga]Ga-TAFC) were evaluated in vitro, and in vivo in a rat lung infection model. Though both siderophores bound ⁶⁸Ga with high affinity, [⁶⁸Ga]Ga-TAFC showed high stability. Furthermore, [⁶⁸Ga]Ga-TAFC exhibited infection site (lung) accumulation in vivo. Later, the same group included [⁶⁸Ga]Ga-TAFC, [⁶⁸Ga]Ga-ferrioxamine E (FOXE), [⁶⁸Ga]Ga-FC, [⁶⁸Ga]Ga-ferrichrome and [⁶⁸Ga]Ga-fusarinine C to evaluate in vitro and pharmacokinetics (PK) in an in vivo healthy murine model (177). They confirmed the suitability of [⁶⁸Ga]Ga-TAFC and [⁶⁸Ga]Ga-FOXE for use in further animal infection models. They then used [⁶⁸Ga]Ga-TAFC and [⁶⁸Ga]Ga-FOXE in in vivo neutropenic rats with pulmonary aspergillosis and used PET/CT to demonstrate their ability to detect infection (178). They also confirmed no uptake of these two potential tracers in human lung tissue by ex vivo uptake assay. However, this study did not consider iron-overload conditions in neutropenic patients in their infection model study, and therefore the effect of not pretreating with iron chelators to reduce free iron (to stop transchelation with TAFC and FOXE) was not evaluated. This could be the reason for the slightly reduced uptake observed in the rat model compared to high in vitro uptake results.

After initial promising results, the same group examined the in vitro specificity of [⁶⁸Ga]Ga-TAFC and [⁶⁸Ga]Ga-FOXE in other microorganisms (bacteria, fungi and yeast) and showed rapid and higher uptake in A. fumigatus, lower uptake in other fungi, and nearly no uptake in other bacteria and yeasts (179). However, in vitro specificity assays in various microorganisms should ideally have been performed before any in vivo A. fumigatus infection model in order to confirm the specificity of the tracer. In vitro results after 90 min showed uptake in A. flavus, A. terreus, and lower uptake in R. oryzae and Fusarium solani compared to A. fumigatus for both tracers, mainly in iron-deficient conditions. [⁶⁸Ga]Ga-FOXE was also shown to be taken up by S. aureus in vitro. In contrast, the abscess model of S. aureus did not show any uptake in vivo. Furthermore, there was noticeable uptake of [⁶⁸Ga]Ga-TAFC and [⁶⁸Ga]Ga-FOXE in the area of induced sterile inflammation. The authors suggested the severe induced inflammation was the reason for this non-specific uptake of both tracers.

Later they also compared the in vivo PK of [⁶⁸Ga]Ga-TAFC and [⁶⁸Ga]Ga-FOXE, ⁶⁸Ga-colloids and [⁶⁸Ga]Ga-citrate in a healthy murine model (180). This showed the same rapid renal excretion and low blood retention of [⁶⁸Ga]Ga-TAFC and [⁶⁸Ga]Ga-FOXE. Some gastrointestinal retention was observed for [⁶⁸Ga]Ga-FOXE, but overall, the results were comparable with colloid and citrate.

Although Petrik et al. showed preclinical progress with [⁶⁸Ga]Ga-TAFC and [⁶⁸Ga]Ga-FOXE, these tracers have not progressed to early phase clinical studies. Instead, they evaluated P. aeruginosa specific siderophore screening for infection diagnostics (181). P. aeruginosa produces different types of siderophores including pyoverdine (PVD) and uses highly efficient FpvA transporters specific for ferripyoverdine uptake. PVD is involved in nutrition, biofilm control, cell-to-cell communication and virulence regulation. [⁶⁸Ga]Ga-PVD-PAO1 (named after the strain name) showed excellent PK properties in healthy mice with rapid renal elimination. Further study in a murine acute respiratory and muscle infection model demonstrated selective accumulation of the radiotracer in infected tissues. The study also demonstrated great sensitivity by enabling the detection of only five viable cells of P. aeruginosa in vivo. Although from published data, aerobactin would be expected to be taken up by P. aeruginosa, their in vitro results showed very low uptake of aerobactin. The in vitro specificity of [⁶⁸Ga]GaPVD-PO1 was good in P. aeruginosa strains (almost no uptake in other tested bacteria and C. albicans). This promising result warrants further clinical studies in human lung infections.

Another study was conducted to develop ⁶⁷Ga-labeled PET tracer with DFO-B for its potential smooth translation to clinical practice to image S. aureus infection (182). Gram-positive S. aureus infection was targeted for in vitro and in vivo uptake of [⁶⁷Ga]Ga-DFO-B, though the authors concluded natural DFO-B is not an ideal candidate to act as an infection imaging agent in patients due its very fast clearance in an in vivo animal infection model. Instead, they developed DFO-derivatives with improved PK. The main aim was to improve the pharmacokinetics of DFO-derived radiotracers with increased uptake in bacteria (S. aureus). When compared with the control [⁶⁷Ga]Ga-16, none of the derivatives shows high in vitro uptake in S. aureus. Additionally, three potential derivatives [⁶⁷Ga]Ga-18, [⁶⁷Ga]Ga-26, and [⁶⁷Ga]Ga-28 were compared with the control in a mouse myositis infection model. Results showed 6 : 1 and 11 : 1 infected and non-infected tissue ratios in control and [⁶⁷Ga]Ga-18, respectively. For the remaining two tracers, the ratio was minimal. However, they did not perform PET imaging to support their findings. Moreover, the ex vivo biodistribution showed high uptake in the small intestine, liver, and gallbladder for all three derivatives. Therefore, these derivatives did not achieve their set goals since the in vitro and in vivo uptake in S. aureus was not greatly improved in these derivatives.

A recent study with [⁶⁸Ga]Ga-DFO-B (Figure 8A) without any chemical modification has shown the potential of a DFO-B-based PET tracer to image infections in vitro caused by P. aeruginosa, S. aureus and S. agalactiae (183) (Figure 8B). They used an in vivo infection model and PET/CT imaging showing infection imaging ability of [⁶⁸Ga]Ga-DFO-B for these bacterial strains. No in vitro uptake was seen for E. coli and C. albicans. More recently, the same group repeated in vitro uptake of [⁶⁸Ga]Ga-DFO-B in A. fumigatus and showed the uptake is pH dependent. They supported their finding with in vivo PET/CT imaging of pulmonary A. fumigatus infection in a rat model (184) (Figure 8C). This finding is contrary to their previous in vitro uptake results, where in vivo infection model was not included. Although this group has achieved repurposing of DFO-B as a broad-spectrum infection imaging tracer experimentally, it necessitates further human studies in improved disease models.

Introduction of fluorescent dye (185) to produce a hybrid imaging modality resulted in rapid uptake in A. fumigatus in vitro, and in an infected lung model in rats showed high fluorescent signal levels that were comparable to a PET/CT scan. This demonstrates the potential applicability of siderophores for hybrid imaging, with possible applications in surgical procedures and bioluminescence in humans (186). A group of researchers in the UK did some preliminary in vitro uptake of [⁶⁸Ga]Ga-ferrichrome C (a fungal siderophore) using E. coli in iron-deficient medium, and in vascular stents incubated with E. coli cells (187). Interestingly, this study performed PET/CT imaging of stents incubated with E. coli vs. sterile stents which shows the applicability of this technique for stent or other medical implant-associated infections. However, there were no details about the methodology in their publication. The same group is now launching an observational clinical study (Clinicaltrials.gov NCT05285072) with [⁶⁸Ga]Ga-DFO-B for VGI imaging titled as “Siderophores for Imaging Infection: A first-in-human pilot study using a tracer ([⁶⁸Ga]Ga-DFO-B) as proof of concept that siderophores can image bacterial infection in vascular grafts” (188). Table 5 summarizes current in vitro and in vivo investigations of ^67/68Ga-siderophores for infection imaging.

Cyclotron produced radiometal Zirconium-89 (⁸⁹Zr) is promising for clinical immune-PET applications, mainly due to its longer half-life that matches the biological half-life of antibodies, and by being safe for human use by virtue of its biological inertness (80). Though the chemistry of ⁸⁹Zr is not very close to Iron, it does behave somewhat similarly to Iron thus it can form a stable radiocomplex with siderophores (190). For infection diagnostics, [⁸⁹Zr]Zr-DFO-B was conjugated with gram-positive specific SAC55, a mAb raised against lipoteichoic acid (LTA), and was used to image an inoculated femur implant in a murine model. When compared to 18FDG and other controls it showed potential differentiation between infection and sterile inflammation (191). Siderophores TAFC and FOXE, selected for A. fumigatus, were also evaluated by labelling with ⁸⁹Zr and compared with [⁶⁸Ga]Ga-TAFC and [⁶⁸Ga]Ga-FOXE to assess the possibility of siderophore-bioconjugates (antibodies/peptides) with ⁸⁹Zr (192). The results showed parallel in vitro and in vivo characteristics with ⁶⁸Ga and ⁸⁹Zr, except [⁸⁹Zr]Zr-FOXE. Another study evaluated the infection imaging potential of ⁸⁹Zr chelators in detecting both S. aureus and P. aeruginosa (193). In an in vivo mouse lung infection model using P. aeruginosa there was no significant differences between infection and control mice as determined by biodistribution.

Another cyclotron produced radiometal, ⁶⁴Cu is of interest as siderophores can chelate metals other than iron. ⁶⁴Cu has been conjugated with the siderophore yersiniabactin (YbT) and in in vitro studies with E. coli it exhibited uptake of [⁶⁴Cu]Cu-YbT (189). This uptake is regulated by the FyuA transporter protein present in E. coli. In vivo studies with E. coli strains UTI and Nissle, K. pneumoniae, P. aeruginosa, and S. aureus in a murine muscle model has demonstrated the uptake of the tracers by all strains except S. aureus (because S. aureus does not possess FyuA transporter protein) (141, 194).

[⁶⁸Ga]Ga-DOTA-TOC, is a PET tracer used for the diagnosis and follow-up of neuroendocrine tumors (NETs) (195). Though this tracer has a high binding affinity to somatostatin receptor subtype 2 (SSTR2), it also binds to somatostatin receptor subtype 5 (SSTR5). Since somatostatin receptors are expressed by activated monocytes, macrophages, and lymphocytes, detection of SSTR2 receptors could potentially be of utility in the diagnosis of IE and other infections. A phase 2 clinical trial (NCT05183555) is underway (196).

A collaborative clinical study with 18FDG PET/CT in S. aureus Bacteremia (PET-SAB) has been launched recently in the UK, registered as NCT05361135 (197). The study aims to include 520 patients and terminate in 2026.

Targeted optical and fluorescence imaging can localize pathogen specific prothrombin activation during S. aureus endocarditis by targeting blood coagulation phenomena (198). This was capable of detecting blood coagulation by S. aureus in vivo, but was unable to visualize the actual bacteria at the site of infection. [⁶⁸Ga]Ga-apo-transferrin also showed capability of S. aureus infection in a murine myositis model (199).

Vancomycin labeled with a fluorophore, IRDye 800CW, was used to detect S. aureus in an in vivo myositis model by injecting engineered luciferase expressing strain of S. aureus. The study demonstrated the potential of fluorophore-labeled vancomycin to detect S. aureus infection with a high signal to noise ratio. However, this strategy would only detect Gram-positive bacteria and would not be able to differentiate between different species of Gram-positive bacteria (200). Fluorescence-PET for S. aureus detection with a human mAb probe has also been investigated (201, 202). None of these are in clinical use yet, as these optical imaging using fluorescence-PET tracers are currently only applicable to visualization of superficial infections due to their limited tissue penetration.