The modern patient is increasingly susceptible to bacterial infections including those due to multi-drug resistant organisms (MDROs). Noninvasive whole-body analysis with pathogen-specific imaging technologies can significantly improve patient outcomes by rapidly identifying a source of infection and monitoring the response to treatment, but no such technology exists clinically. Methods We systematically screened 961 random, radiolabeled molecules in silico as substrates for essential metabolic pathways in bacteria, followed by in vitro uptake in representative bacteria – Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and mycobacteria. Fluorine-labeled analogs, that could be developed as positron emission tomography (PET)-based imaging tracers, were evaluated in a murine myositis model. Results We identified three novel, non-toxic molecules demonstrating selective bacterial uptake: para-aminobenzoic acid (PABA), with uptake in all representative bacteria including Mycobacterium tuberculosis; mannitol, with selectively uptake in S. aureus and E. coli; and sorbitol, accumulating only in E. coli. None accumulated in mammalian cells or heat-killed bacteria, suggesting metabolism-derived specificity. In addition to an extended bacterial panel of laboratory strains, all three molecules rapidly accumulated in respective clinical isolates of interest including MDROs such as methicillin resistant S. aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing, and carbapenem-resistant Enterobacteriaceae. In a murine myositis model, fluorine-labeled analogs of all three molecules could rapidly detect and differentiate infection sites from sterile inflammation in mice (P=0.03). Finally, 2-deoxy-2-[F-18]fluoro-D-sorbitol (18F-FDS) can be easily synthesized from 2-deoxy-2-[F-18]fluoro-D-glucose (18F-FDG). PET, utilizing 18F-FDS synthesized using current good manufacturing practice, could rapidly differentiate true infection from sterile inflammation to selectively localize E. coli infection in mice. Conclusion We have developed a systematic approach that exploits unique biochemical pathways in bacteria to develop novel pathogen-specific imaging tracers. These tracers have significant potential for clinical translation to specifically detect and localize a broad range of bacteria, including MDROs.

Background:The medical treatment of periprosthetic joint infection (PJI) involves prolonged systemic antibiotic courses, often with suboptimal clinical outcomes including increased morbidity and health-care costs. Oral and intravenous monotherapies and combination antibiotic regimens were evaluated in a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) PJI.Methods:Oral linezolid with or without oral rifampin, intravenous vancomycin with oral rifampin, intravenous daptomycin or ceftaroline with or without oral rifampin, oral doxycycline, or sham treatment were administered at human-exposure doses for 6 weeks in a mouse model of PJI. Bacterial burden was assessed by in vivo bioluminescent imaging and ex vivo counting of colony-forming units (CFUs), and reactive bone changes were evaluated with radiographs and micro-computed tomography (μCT) imaging.Results:Oral-only linezolid-rifampin and all intravenous antibiotic-rifampin combinations resulted in no recoverable bacteria and minimized reactive bone changes. Although oral linezolid was the most effective monotherapy, all oral and intravenous antibiotic monotherapies failed to clear infection or prevent reactive bone changes.Conclusions:Combination antibiotic-rifampin regimens, including oral-only linezolid-rifampin and the newer ceftaroline-rifampin combinations, were highly effective and more efficacious than monotherapies when used against a preclinical MRSA PJI.Clinical Relevance:This study provides important preclinical evidence to better optimize future antibiotic therapy against PJIs. In particular, the oral-only linezolid-rifampin option might reduce venous access complications and health-care costs.

Background:Mosquito borne diseases (MBDs) are major public health problem in India. State of Delhi is endemic for dengue and other MBDs. The increasing incidence of MBDs in Delhi in recent years warrants a pro-active approach for their prevention. Knowledge and use of personal protective measures (PPMs) presents an effective strategy for prevention and control of MBDs.Aim:The present study was conducted to assess the knowledge and use of PPMs against MBDs in an urban resettlement colony of Delhi.Subjects and Methods:It was a cross-sectional study carried out in a resettlement colony of Delhi. A total of 100 families were selected by systematic random sampling. Data was collected using semi-structured questionnaire and supplemented by spot survey by the investigator in the community. The results were analyzed in SPSS version 16.0 (Chicago Illinios, USA).Results:Out of the 100 respondents, 65% (65/100), 58%(58/100) and 13% (13/100) had heard about dengue, malaria and chikungunya, respectively. Nearly, one-fifth (20/100; 20%) of the participants reported incorrect breeding sites for mosquitoes. The knowledge regarding PPMs was very high (93/100; 93%) and about (90/100; 90%) families were actually using at least one of the PPMs. However, very few families were using them correctly (1/90; 1.1%) and adequately (5/90; 5.6%). The most common PPM being used by the study population was liquid vaporizers (54/90; 60%). Nearly one-third (29/90; 32.2%) of the participants reported side-effects due to PPMs with irritation to smell being the most common reported side-effect. On house visit, adult mosquitoes were seen in 67% (67/100) of the houses, while potential mosquito breeding sites were found in and around 56% (56/100) houses.Conclusions:There were crucial gaps in knowledge and practices of participants with regard to prevention and control of MBDs. Thus, there is a need to intensify efforts toward creating public knowledge and mobilizing community about correct use of preventive measures against MBDs.

The antileprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impacts of duration, dose, and companion drugs on the treatment-shortening activity of clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) 6 months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in the lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when coadministered with first-line drugs continuously throughout treatment and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that clofazimine at low exposures may have negative impacts on treatment outcomes, an effect that was evident only after the first 3 months of treatment. These data provide a sound evidence base to inform clofazimine dosing strategies to optimize the antituberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow the full evaluation of drugs administered in combination over long durations.