Written in the Blood: Why Wait?

A timely diagnosis can be all that stands between life and death. A patient presenting with fever, fatigue and aches may be suffering from a systemic infection, potentially requiring immediate treatment. The most appropriate treatment will depend on the nature of the infection, but this is not always immediately apparent. Turning to the diagnostic toolkit, there is the option of blood culture - if the physician suspects a bacterial or yeast infection, blood is taken from the patient, and incubated under conditions that allow certain microbes to grow. If growth is observed, further tests are performed to determine the type of organism present, and its sensitivity to antibiotics. The whole process may take up to a week, seven long days that the worst afflicted may not have.
Two years ago, Ying Taur, a physician at the Memorial Sloan-Kettering Cancer Center, reported that the time taken to positively identify a blood culture was associated with increased mortality in hospitalised cancer patients with fungal infections (published in Antimicrobial Agents and Chemotherapy; Taur et al. 2010 Jan;54(1):184-90). In the same study, the authors stressed the need for a swifter alternative to blood culture, to save lives. Now, thanks to work conducted by Ting-Yu Liu, Yuh-Lin Wang and their colleagues at Academia Sinica, Taipei, we have taken a large step towards that alternative.
In a paper recently published in the journal Nature Communications (Liu et al. 2011 Nov 15;2:538), Liu and Wang describe a technique to capture bacteria from blood samples, in such a way that they can be directly analysed by spectroscopy. This builds on earlier work, which demonstrated that different types of bacteria could be distinguished by a spectroscopic technique: surface-enhanced Raman spectroscopy.
Traditional Raman spectroscopy involves shining a light on the sample to be analysed. Photons (light particles) are absorbed, and subsequently re-emitted by the sample - some of these secondary photons possess a wavelength different to that of the originals. This "inelastic" (referring to the change in wavelength) scattering of photons is known as Raman scattering. The emitted photons are collected with a lens, and any photons with a wavelength close to the originals are filtered out, leaving only the Raman signal. From the change in wavelength observed in the Raman signal, information about the molecular structure of the sample can be gleaned. As the name suggests, surface-enhanced Raman spectroscopy (or SERS) uses a special surface to enhance the Raman signal, typically molecules adsorbed (adhered) to a rough metallic surface.
Together with collaborators at National Taiwan University, Liu and Wang coated a SERS substrate with the antibiotic vancomycin (Van), which binds to the bacterial cell wall. Bacteria are concentrated into the Van-coated region, resulting in a thousand-fold increase in capture. Importantly, Van-coating does not substantially affect the Raman signal of the bacteria tested, and it also dramatically increases the SERS signal. The authors speculate that this increase may arise from Van pulling the bacterial cell wall towards the metallic substrate, thereby filling up the gaps that exist between particles on the metal. These gaps act as 'hot spots' for the enhancement of Raman scattering, and therefore bringing the bacteria close to these sites may account for the greater signal. The Van coating also decreases the affinity of blood cells to the metallic surface, while increasing the affinity of bacteria. This study also demonstrates that VAN-resistant and susceptible bacteria produce different Raman signals in this system, leaving open the prospect of rapid determination of antibiotic sensitivity.
The implications of this rapid detection system are far-reaching: the authors note that with minor modifications, the protocol could be adapted to capture virus particles as well. Furthermore, this protocol enables researchers to concentrate bacteria from not just blood, but any environmental sample. As we are unable to culture all but a fraction of bacterial species, such Van-capture technology may expedite our ability to not only identify new bacterial species by genome sequencing, but also to swiftly identify contaminating organisms within drinking water.
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