Noninvasive optical and nuclear imaging of Staphylococcus-specific infection with a human monoclonal antibody-based probe

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, (89)Zirconium-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 antibod

In vitro imaging of bacteria using (18)F-fluorodeoxyglucose micro positron emission tomography

Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose ((18)F-FDG) can be applied to detect infection and inflammation. However, it was so far not known to what extent bacterial pathogens may contribute to the PET signal. Therefore, we investigated whether clinical isolates of frequently encountered bacterial pathogens take up (18)F-FDG in vitro, and whether FDG inhibits bacterial growth as previously shown for 2-deoxy-glucose. 22 isolates of Gram-positive and Gram-negative bacterial pathogens implicated in fever and inflammation were incubated with (18)F-FDG and uptake of (18)F-FDG was assessed by gamma-counting and µPET imaging. Possible growth inhibition by FDG was assayed with Staphylococcus aureus and the Gram-positive model bacterium Bacillus subtilis. The results show that all tested isolates accumulated (18)F-FDG actively. Further, (18)F-FDG uptake was hampered in B. subtilis pts mutants impaired in glucose uptake. FDG inhibited growth of S. aureus and B. subtilis only to minor extents, and this effect was abrogated by pts mutations in B. subtilis. These observations imply that bacteria may contribute to the signals observed in FDG-PET infection imaging in vivo. Active bacterial FDG uptake is corroborated by the fact that the B. subtilis phosphotransferase system is needed for (18)F-FDG uptake, while pts mutations protect against growth inhibition by FDG

High HIV incidence among MSM prescribed postexposure prophylaxis, 2000-2009: indications for ongoing sexual risk behaviour

Objective: To determine (trends in) HIV incidence among MSM who have recently had postexposure prophylaxis (PEP) prescribed in Amsterdam, compared with MSM participating in the Amsterdam Cohort Studies (ACS). Design and methods: We used data from MSM who were prescribed PEP in Amsterdam between 2000 and 2009, who were HIV-negative at the time of PEP prescription and had follow-up HIV testing 3 and/or 6 months after PEP prescription (n = 395). For comparison, cohort data from MSM participating in the ACS in the same period were used (n 782). Poisson log-linear regression analyses were performed to model trends in HIV incidence and identify differences in HIV incidence between both cohorts at different time points. Results: Between 2000 and 2009, among MSM who were prescribed PEP, an overall HIV incidence of 6.4 [95% confidence interval (CI) 3.4-11.2] per 100 person-years was found, compared with an HIV incidence of 1.6 (95% CI 1.3-2.1) per 100 person-years among MSM participating in the ACS (P <0.01). In both cohorts, an increasing trend in HIV incidence over time was observed [incidence rate ratio (IRRper calendar year) 1.3 (95% CI 0.9-1.7) and 1.1 (95% CI 1.0-1.2) among MSM prescribed PEP and MSM of the ACS, respectively]. The difference in HIV incidence between both cohorts was most evident in more recent years [IRRPEP versus ACS in 2009 4.8 (95% CI 2.0-11.5)]. Conclusion: Particularly in more recent years, MSM recently prescribed PEP had a higher HIV incidence compared with MSM participating in the ACS, indicating ongoing sexual risk behaviour. (C) 2012 Wolters Kluwer Health broken vertical bar Lippincott Williams & Wilkin

Publisher Correction: In vitro imaging of bacteria using 18F-fluorodeoxyglucose micro positron emission tomography

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Fighting Staphylococcus aureus infections with light and photoimmunoconjugates

Infections caused by multidrug-resistant Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), are responsible for high mortality and morbidity worldwide. Resistant lineages were previously confined to hospitals but are now also causing infections among healthy individuals in the community. It is therefore imperative to explore therapeutic avenues that are less prone to raise drug resistance compared with today’s antibiotics. An opportunity to achieve this ambitious goal could be provided by targeted antimicrobial photodynamic therapy (aPDT), which relies on the combination of a bacteria-specific targeting agent and light-induced generation of ROS by an appropriate photosensitizer. Here, we conjugated the near-infrared photosensitizer IRDye700DX to a fully human mAb, specific for the invariantly expressed staphylococcal antigen immunodominant staphylococcal antigen A (IsaA). The resulting immunoconjugate 1D9-700DX was characterized biochemically and in preclinical infection models. As demonstrated in vitro, in vivo, and in a human postmortem orthopedic implant infection model, targeted aPDT with 1D9-700DX is highly effective. Importantly, combined with the nontoxic aPDT-enhancing agent potassium iodide, 1D9-700DX overcomes the antioxidant properties of human plasma and fully eradicates high titers of MRSA. We show that the developed immunoconjugate 1D9-700DX targets MRSA and kills it upon illumination with red light, without causing collateral damage to human cells