IMAGING
Bacterial Imaging Comes of Age Xiaojian Wang and Niren Murthy*
CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
Enterobacteriaceae, a type of highly virulent Gram-negative bacteria, can be imaged in vivo in animals via positron emission tomography with 18F-sorbitol (Weinstein et al., this issue).
Bacterial infections are a major cause of mortality and morbidity in the world and afect every aspect of medicine. For example, in the United States bacterial infections cause more deaths per year than HIV/ AIDS, breast cancer, and prostate cancer combined (www.nigms.nih.gov/Education/ Pages/factsheet_sepsis.aspx). Furthermore, in the United States approximately 2 million patients per year acquire a nosocomial infection, and the Centers for Disease Control (CDC) estimates that the fnancial impact of these infections exceeds 5 billion dollars annually (1). In addition, the medical burden generated from infections is expected to rise dramatically in the next 10 to 20 years, owing to antibacterial resistance and the anticipated increase in the number of immunocompromised patients and patients receiving implanted medical devices. In the UK, the frequency of drug-resistant bacteria increased 20-fold in the past 10 years, making routine infections, such as communityacquired urinary tract infections, now challenging to treat (2). Despite the staggering economic and personal costs, almost no progress has been made on diagnosing or treating bacterial infections, with the current methods of diagnosing infections having remained stagnant for about 50 years. In this issue of Science Translational Medicine, Weinstein and colleagues reveal a new approach to sensitively diagnose and track whole-body infections in mice caused by Enterobacteriaceae, a type of highly virulent Gram-negative bacterial infection, by using positron emission tomography (PET), a commonly available imaging technique available to clinicians (3). DIAGNOSING INFECTION Te diagnosis of an infection is currently made on the basis of clinical criteria, including the physical exam and microbial cultures. Culturing infectious bacteria, Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA. *Corresponding author. E-mail: [email protected]
from a diagnostic standpoint, is problematic because these methods can only detect late-stage infections that are challenging to treat (4). Imaging infections with computed tomography (CT), magnetic resonance imaging (MRI), or PET—imaging technologies widely used in the clinic—has tremendous potential for improving infection diagnosis but has been limited by the current state of the technologies themselves and a lack of bacterial-specifc contrast agents. For instance, ultrasound, CT, MRI, and PET can only image sof-tissue changes or infammation consistent with, but not indicative of, infection. PET has been used to image bacterial infections clinically, ofen in conjunction with CT, by using the approved probe 2-[18F] fuorodeoxyglucose (FDG) to identify infammation because FDG is more readily taken up by infammatory cells. FDG imaging of infections has tremendous potential because of the high sensitivity of PET imaging, giving it the potential ability to spatially localize infections in patients at an early stage. However, FDG sufers from two issues: low sensitivity due to the nonspecifc nature of the approach because FDG is taken up by all cells capable of metabolizing glucose, and an inability to distinguish between sterile infammation from infammation caused by infection (5). Tus, there is an unmet clinical need to develop imaging technologies with high sensitivity and specifcity to detect bacteria at the earliest possible stages of infection. Such a technology would have the potential to reduce morbidity, mortality, and health care costs. BACTERIAL PROBES Recently, three diferent PET contrast agents were developed to image bacterial infections in vivo, via PET: 18F-maltose (6), 18 F-maltohexaose (7), and from Weinstein et al., 18F-2-fuorodeoxy sorbitol (FDS) (3). Tese new contrast agents could specifcally target bacteria in vivo for the frst time by targeting transporters and metabolic path-
ways that are unique to bacteria and not present in mammalian cells. Te frst two probes are based on targeting the maltodextrin transporter, which is specifc to bacteria (Fig. 1) (8). Maltodextrin transporters internalize substrates at very high rates and tolerate large modifcations to their substrates, such as a PET probe attached to maltose or maltohexose. Tis class of probes can target all bacteria and does not distinguish between Gram-negative and -positive bacteria (6–8). Te third probe, FDS, described in this issue of Science Translational Medicine (3), is the frst probe capable of distinguishing between Gram-positive and -negative infections and targets a specifc class of Gramnegative bacteria, the Enterobacteriaceae (Fig. 1). Enterobacteriaceae are a family of rod-shaped bacteria and include dangerous pathogens such as carbapenemase-resistant Escherichia coli, Klebsiella, and Yersinia pestis (CREs). CREs are among the most dreaded class of infectious diseases, and treatment of these infections difers from treatment of Gram-positive infections. For example, Gram-positive infections can be treated with vancomycin, whereas this class of antibiotics is inactive against Enterobacteriaceae, which need to be treated with carbapenems or antibiotics based on local resistance trends. Terefore, being able to identify CREs in patients at an early stage has the potential to substantially improve their treatment. Weinstein et al. observed that Enterobacteriaceae exclusively express the enzyme sorbitol-6-phosphate dehydrogenase, which is the enzyme responsible for initiating sorbitol metabolism, and thus hypothesized that the uptake of sorbitol by Enterobacteriaceae would be higher than that of mammalian cells and other types of bacteria, presumably through the glycerol difusion facilitator (glpF) (Fig. 1) (9). FDS can be made in one step from commercially available FDG, making its translation into clinical radiochemistry labs straightforward (10). Te authors therefore investigated the uptake of FDS by Enterobacteriaceae versus mammalian cells and observed a 1000-fold diference in uptake. In vivo in a mouse model of E. coli infection, FDS-PET was used to detect as few as 106 colony-forming units (CFUs) of bacteria in mice, which is 1 to 2 orders of magnitude more sensitive than FDG and other nonspecifc imaging technologies. FDS-PET could also distinguish between
www.ScienceTranslationalMedicine.org 22 October 2014 Vol 6 Issue 259 259fs43
1
Downloaded from stm.sciencemag.org on April 28, 2015
FOCUS
Gram-negative bacteria
Gram-negative and -positive bacteria
Sorbitol PET probe
Infammation
glpF transporter
Maltose or maltohexaose ATP
Maltodextrin transporter Infection
Internalized PET contrast agents
Fig. 1. Bacterial infection imaging. (A) FDS internalization through glpF. Other transporters may contribute to the uptake of sorbitol by bacteria as well. Mammalian cells do not take up sorbitol. (B) Maltodextrin transporter–mediated uptake of 18F-maltose and 18F-maltohexaose. Neither glpF nor maltodextrin transporter is expressed by mammalian cells, thus the specificity in distinguishing bacterial infections from general inflammation.
sterile infammation and infection and was substantially better at specifcally imaging infections than was FDG. Te recently described 18F-maltohexaose and 18F-maltose have similar specifcities and sensitivities to FDS. However, FDS is the only probe capable of distinguishing Gram-negative from Gram-positive infections. Weinstein et al. demonstrated a 10-fold diference in selectivity between Enterobacteriaceae (Gram-negative) and Staphylococcus aureus (Gram-positive), which would be useful in proper prescription of antibiotics at an early stage of the infection. Last, Weinstein et al. investigated the ability of FDS to image drug resistance. CREs are a particularly difcult challenge in the clinic because of the lack of available antibiotics, and the presence of CREs generally means that drastic, sometimes unconventional treatment approaches need to be considered, including use of toxic antibiotics, such as colistin. At present, the only way to identify drug resistance is to culture the bacteria and do antibiotic susceptibility testing. However, this method takes several days to perform, which is generally too late to afect treatment, and frequently cannot be accomplished because of challenges in acquiring the bacteria from the patient. Weinstein et al. were able to demonstrate that FDS can distinguish between infection from cefriaxone-resistant Enterobacteriaceae versus infection from cefriaxonesusceptible Enterobacteriaceae. In their
experiment, they infected mice with either drug-resistant or wild-type E. coli, imaged with FDS, treated with cefriaxone, and then imaged with FDS again. Tey observed that the PET signal from the resistant bacteria increased as a result of their ability to survive the treatment and multiply, whereas the PET signal from the susceptible bacteria decreased as a result of their killing and clearance. Te ability to rapidly measure drug resistance has the potential to substantially improve treatment. For example, in the case of sepsis, patient survival can increase by as much as 50% if drug resistance is identifed at an early stage. FUTURE PROSPECTS FOR BUG IMAGING Te report by Weinstein et al. (3), along with those by Gowrishankar et al. (6) and Ning et al. (7, 8), represent major advances in the feld of bacterial imaging. All of these probes can distinguish between infection and in%ammation and can identify bacterial drug resistance. Tus, in the future, a patient suspected of having an infection could be imaged with the maltodextrinbased probes to determine whether there is a bacterial infection, and by using FDS, they can identify the type of bacteria so that treatment can be tailored appropriately and rapidly. In addition, all three probes are made in one step, via syntheses routinely used in clinical radiochemistry labs, and are based on small molecules that have
excellent biocompatibility, maltose, maltohexaose, and sorbitol. In addition, PET imaging is routinely done in the clinic, and the cost of conducting PET imaging clinical trials is fairly cheap; therefore, these probes have the potential to translate on the time scale of 5 to 10 years. However, thousands of PET imaging probes have been generated that looked promising in mice but never made it into clinical practice. 18F-Maltose, 18F-maltohexaose, and FDS were investigated in animal models that used metabolically active bacteria, which should internalize the probes much faster than bacteria in protective bioflms. Tis could be a serious limitation in application because bioflms represent a major class of infections. In addition, it is unclear what the actual CFU number is in a human infection, and therefore it is impossible to determine whether FDS and other probes have the sensitivity needed to detect early-stage infections (although it appears that this may be possible based on the limited CFU data available). In addition, the nonspecifc clearance of these probes could be substantially diferent in rodents and humans, and the variability in imaging from human to human could be large, given the genetic heterogeneity of the human population, as opposed to clones of mice. Te metabolism of these probes in humans could also be a potential roadblock to clinical success because de%uorination of the probes or premature hydrolysis by enzymes in the serum may lead to high background. Last, the exact clinical context in which the cost of PET imaging of an infection would be warranted is unclear. Infection imaging needs to result in a very specifc consequence regarding treatment, otherwise insurance companies will not reimburse the procedure. We imagine that PET imaging will be desired for implant infections, endocarditis (infection of heart), and diseases that require quick diagnoses to prevent mortality, such as sepsis, and those that chart a treatment course, such as distinguishing pneumonia from cancer. Bacterial infections impose a substantial burden on our health care system and are increasing at an alarming rate. An imagingbased approach to diagnosing infection early, specifcally, sensitively, and confdently has the potential to afect almost all aspects of medicine but has remained elusive because of a lack of strategies for targeting bacteria. Te results presented in
www.ScienceTranslationalMedicine.org 22 October 2014 Vol 6 Issue 259 259fs43
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Downloaded from stm.sciencemag.org on April 28, 2015
FOCUS
FOCUS
REFERENCES AND NOTES 1. D. Reed, S. A. Kemmerly, Infection control and prevention: A review of hospital-acquired infections and the economic implications. Ochsner J. 9, 27–31 (2009). 2. D. M. Livermore, Linezolid in vitro: Mechanism and antibacterial spectrum. J. Antimicrob. Chemother. 51 (suppl. 2), ii9–ii16 (2003). 3. E. A. Weinstein, A. A. Ordonez, V. P. DeMarco, A. M. Murawski, S. Pokkali, E. M. MacDonald, M. Klunk, R. C. Mease, M. G. Pomper, S. K. Jain, Imaging Enterobacteriaceae infection in vivo with 18F-fluorodeoxysorbitol positron emission tomography. Sci. Transl. Med. 6, 259ra146 (2014).
4. M. L. Wilson, W. Winn, Laboratory diagnosis of bone, joint, soft-tissue, and skin infections. Clin. Infect. Dis. 46, 453–457 (2008). 5. A. W. J. M. Glaudemans, E. F. J. de Vries, F. Galli, R. A. J. O. Dierckx, R. H. J. A. Slart, A. Signore, The use of 18F-FDGPET/CT for diagnosis and treatment monitoring of inflammatory and infectious diseases. Clin. Dev. Immunol. 2013, 623036 (2013). 6. G. Gowrishankar, M. Namavari, E. B. Jouannot, A. Hoehne, R. Reeves, J. Hardy, S. S. Gambhir, Investigation of 6-[18F]fluoromaltose as a novel PET tracer for imaging bacterial infection. PLOS One 9, e107951 (2014). 7. X. Ning, W. Seo, S. Lee, K. Takemiya, M. Rafi, X. Feng, D. Weiss, X. Wang, L. Williams, V. M. Camp, M. Eugene, W. R. Taylor, M. Goodman, N. Murthy, Fluorine-18 labeled maltohexaose images bacterial infections by PET. Angew. Chem. Int. Ed. 10.1002/anie.201408533R1 (2014). 8. X. Ning, S. Lee, Z. Wang, D. Kim, B. Stubblefield, E. Gilbert,
N. Murthy, Maltodextrin-based imaging probes detect bacteria in vivo with high sensitivity and specificity. Nat. Mater. 10, 602–607 (2011). 9. K. B. Heller, E. C. Lin, T. H. Wilson, Substrate specificity and transport properties of the glycerol facilitator of Escherichia coli. J. Bacteriol. 144, 274–278 (1980). 10. Z. B. Li, Z. Wu, Q. Cao, D. W. Dick, J. R. Tseng, S. S. Gambhir, X. Chen, The synthesis of 18F-FDS and its potential application in molecular imaging. Mol. Imaging Biol. 10, 92–98 (2008). Competing interests: N.M. is an equity holder in Microbial Imaging, a company focused on using maltodextrins to target bacterial infections. 10.1126/scitranslmed.3010746 Citation: X. Wang, N. Murthy, Bacterial imaging comes of age. Sci. Transl. Med. 6, 259fs43 (2014).
Downloaded from stm.sciencemag.org on April 28, 2015
this issue of Science Translational Medicine, and the other two recent publications, suggest that a new chapter in bacterial imaging has begun.
www.ScienceTranslationalMedicine.org 22 October 2014 Vol 6 Issue 259 259fs43
3
Bacterial Imaging Comes of Age Xiaojian Wang and Niren Murthy*
CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
Enterobacteriaceae, a type of highly virulent Gram-negative bacteria, can be imaged in vivo in animals via positron emission tomography with 18F-sorbitol (Weinstein et al., this issue).
Bacterial infections are a major cause of mortality and morbidity in the world and afect every aspect of medicine. For example, in the United States bacterial infections cause more deaths per year than HIV/ AIDS, breast cancer, and prostate cancer combined (www.nigms.nih.gov/Education/ Pages/factsheet_sepsis.aspx). Furthermore, in the United States approximately 2 million patients per year acquire a nosocomial infection, and the Centers for Disease Control (CDC) estimates that the fnancial impact of these infections exceeds 5 billion dollars annually (1). In addition, the medical burden generated from infections is expected to rise dramatically in the next 10 to 20 years, owing to antibacterial resistance and the anticipated increase in the number of immunocompromised patients and patients receiving implanted medical devices. In the UK, the frequency of drug-resistant bacteria increased 20-fold in the past 10 years, making routine infections, such as communityacquired urinary tract infections, now challenging to treat (2). Despite the staggering economic and personal costs, almost no progress has been made on diagnosing or treating bacterial infections, with the current methods of diagnosing infections having remained stagnant for about 50 years. In this issue of Science Translational Medicine, Weinstein and colleagues reveal a new approach to sensitively diagnose and track whole-body infections in mice caused by Enterobacteriaceae, a type of highly virulent Gram-negative bacterial infection, by using positron emission tomography (PET), a commonly available imaging technique available to clinicians (3). DIAGNOSING INFECTION Te diagnosis of an infection is currently made on the basis of clinical criteria, including the physical exam and microbial cultures. Culturing infectious bacteria, Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA. *Corresponding author. E-mail: [email protected]
from a diagnostic standpoint, is problematic because these methods can only detect late-stage infections that are challenging to treat (4). Imaging infections with computed tomography (CT), magnetic resonance imaging (MRI), or PET—imaging technologies widely used in the clinic—has tremendous potential for improving infection diagnosis but has been limited by the current state of the technologies themselves and a lack of bacterial-specifc contrast agents. For instance, ultrasound, CT, MRI, and PET can only image sof-tissue changes or infammation consistent with, but not indicative of, infection. PET has been used to image bacterial infections clinically, ofen in conjunction with CT, by using the approved probe 2-[18F] fuorodeoxyglucose (FDG) to identify infammation because FDG is more readily taken up by infammatory cells. FDG imaging of infections has tremendous potential because of the high sensitivity of PET imaging, giving it the potential ability to spatially localize infections in patients at an early stage. However, FDG sufers from two issues: low sensitivity due to the nonspecifc nature of the approach because FDG is taken up by all cells capable of metabolizing glucose, and an inability to distinguish between sterile infammation from infammation caused by infection (5). Tus, there is an unmet clinical need to develop imaging technologies with high sensitivity and specifcity to detect bacteria at the earliest possible stages of infection. Such a technology would have the potential to reduce morbidity, mortality, and health care costs. BACTERIAL PROBES Recently, three diferent PET contrast agents were developed to image bacterial infections in vivo, via PET: 18F-maltose (6), 18 F-maltohexaose (7), and from Weinstein et al., 18F-2-fuorodeoxy sorbitol (FDS) (3). Tese new contrast agents could specifcally target bacteria in vivo for the frst time by targeting transporters and metabolic path-
ways that are unique to bacteria and not present in mammalian cells. Te frst two probes are based on targeting the maltodextrin transporter, which is specifc to bacteria (Fig. 1) (8). Maltodextrin transporters internalize substrates at very high rates and tolerate large modifcations to their substrates, such as a PET probe attached to maltose or maltohexose. Tis class of probes can target all bacteria and does not distinguish between Gram-negative and -positive bacteria (6–8). Te third probe, FDS, described in this issue of Science Translational Medicine (3), is the frst probe capable of distinguishing between Gram-positive and -negative infections and targets a specifc class of Gramnegative bacteria, the Enterobacteriaceae (Fig. 1). Enterobacteriaceae are a family of rod-shaped bacteria and include dangerous pathogens such as carbapenemase-resistant Escherichia coli, Klebsiella, and Yersinia pestis (CREs). CREs are among the most dreaded class of infectious diseases, and treatment of these infections difers from treatment of Gram-positive infections. For example, Gram-positive infections can be treated with vancomycin, whereas this class of antibiotics is inactive against Enterobacteriaceae, which need to be treated with carbapenems or antibiotics based on local resistance trends. Terefore, being able to identify CREs in patients at an early stage has the potential to substantially improve their treatment. Weinstein et al. observed that Enterobacteriaceae exclusively express the enzyme sorbitol-6-phosphate dehydrogenase, which is the enzyme responsible for initiating sorbitol metabolism, and thus hypothesized that the uptake of sorbitol by Enterobacteriaceae would be higher than that of mammalian cells and other types of bacteria, presumably through the glycerol difusion facilitator (glpF) (Fig. 1) (9). FDS can be made in one step from commercially available FDG, making its translation into clinical radiochemistry labs straightforward (10). Te authors therefore investigated the uptake of FDS by Enterobacteriaceae versus mammalian cells and observed a 1000-fold diference in uptake. In vivo in a mouse model of E. coli infection, FDS-PET was used to detect as few as 106 colony-forming units (CFUs) of bacteria in mice, which is 1 to 2 orders of magnitude more sensitive than FDG and other nonspecifc imaging technologies. FDS-PET could also distinguish between
www.ScienceTranslationalMedicine.org 22 October 2014 Vol 6 Issue 259 259fs43
1
Downloaded from stm.sciencemag.org on April 28, 2015
FOCUS
Gram-negative bacteria
Gram-negative and -positive bacteria
Sorbitol PET probe
Infammation
glpF transporter
Maltose or maltohexaose ATP
Maltodextrin transporter Infection
Internalized PET contrast agents
Fig. 1. Bacterial infection imaging. (A) FDS internalization through glpF. Other transporters may contribute to the uptake of sorbitol by bacteria as well. Mammalian cells do not take up sorbitol. (B) Maltodextrin transporter–mediated uptake of 18F-maltose and 18F-maltohexaose. Neither glpF nor maltodextrin transporter is expressed by mammalian cells, thus the specificity in distinguishing bacterial infections from general inflammation.
sterile infammation and infection and was substantially better at specifcally imaging infections than was FDG. Te recently described 18F-maltohexaose and 18F-maltose have similar specifcities and sensitivities to FDS. However, FDS is the only probe capable of distinguishing Gram-negative from Gram-positive infections. Weinstein et al. demonstrated a 10-fold diference in selectivity between Enterobacteriaceae (Gram-negative) and Staphylococcus aureus (Gram-positive), which would be useful in proper prescription of antibiotics at an early stage of the infection. Last, Weinstein et al. investigated the ability of FDS to image drug resistance. CREs are a particularly difcult challenge in the clinic because of the lack of available antibiotics, and the presence of CREs generally means that drastic, sometimes unconventional treatment approaches need to be considered, including use of toxic antibiotics, such as colistin. At present, the only way to identify drug resistance is to culture the bacteria and do antibiotic susceptibility testing. However, this method takes several days to perform, which is generally too late to afect treatment, and frequently cannot be accomplished because of challenges in acquiring the bacteria from the patient. Weinstein et al. were able to demonstrate that FDS can distinguish between infection from cefriaxone-resistant Enterobacteriaceae versus infection from cefriaxonesusceptible Enterobacteriaceae. In their
experiment, they infected mice with either drug-resistant or wild-type E. coli, imaged with FDS, treated with cefriaxone, and then imaged with FDS again. Tey observed that the PET signal from the resistant bacteria increased as a result of their ability to survive the treatment and multiply, whereas the PET signal from the susceptible bacteria decreased as a result of their killing and clearance. Te ability to rapidly measure drug resistance has the potential to substantially improve treatment. For example, in the case of sepsis, patient survival can increase by as much as 50% if drug resistance is identifed at an early stage. FUTURE PROSPECTS FOR BUG IMAGING Te report by Weinstein et al. (3), along with those by Gowrishankar et al. (6) and Ning et al. (7, 8), represent major advances in the feld of bacterial imaging. All of these probes can distinguish between infection and in%ammation and can identify bacterial drug resistance. Tus, in the future, a patient suspected of having an infection could be imaged with the maltodextrinbased probes to determine whether there is a bacterial infection, and by using FDS, they can identify the type of bacteria so that treatment can be tailored appropriately and rapidly. In addition, all three probes are made in one step, via syntheses routinely used in clinical radiochemistry labs, and are based on small molecules that have
excellent biocompatibility, maltose, maltohexaose, and sorbitol. In addition, PET imaging is routinely done in the clinic, and the cost of conducting PET imaging clinical trials is fairly cheap; therefore, these probes have the potential to translate on the time scale of 5 to 10 years. However, thousands of PET imaging probes have been generated that looked promising in mice but never made it into clinical practice. 18F-Maltose, 18F-maltohexaose, and FDS were investigated in animal models that used metabolically active bacteria, which should internalize the probes much faster than bacteria in protective bioflms. Tis could be a serious limitation in application because bioflms represent a major class of infections. In addition, it is unclear what the actual CFU number is in a human infection, and therefore it is impossible to determine whether FDS and other probes have the sensitivity needed to detect early-stage infections (although it appears that this may be possible based on the limited CFU data available). In addition, the nonspecifc clearance of these probes could be substantially diferent in rodents and humans, and the variability in imaging from human to human could be large, given the genetic heterogeneity of the human population, as opposed to clones of mice. Te metabolism of these probes in humans could also be a potential roadblock to clinical success because de%uorination of the probes or premature hydrolysis by enzymes in the serum may lead to high background. Last, the exact clinical context in which the cost of PET imaging of an infection would be warranted is unclear. Infection imaging needs to result in a very specifc consequence regarding treatment, otherwise insurance companies will not reimburse the procedure. We imagine that PET imaging will be desired for implant infections, endocarditis (infection of heart), and diseases that require quick diagnoses to prevent mortality, such as sepsis, and those that chart a treatment course, such as distinguishing pneumonia from cancer. Bacterial infections impose a substantial burden on our health care system and are increasing at an alarming rate. An imagingbased approach to diagnosing infection early, specifcally, sensitively, and confdently has the potential to afect almost all aspects of medicine but has remained elusive because of a lack of strategies for targeting bacteria. Te results presented in
www.ScienceTranslationalMedicine.org 22 October 2014 Vol 6 Issue 259 259fs43
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Downloaded from stm.sciencemag.org on April 28, 2015
FOCUS
FOCUS
REFERENCES AND NOTES 1. D. Reed, S. A. Kemmerly, Infection control and prevention: A review of hospital-acquired infections and the economic implications. Ochsner J. 9, 27–31 (2009). 2. D. M. Livermore, Linezolid in vitro: Mechanism and antibacterial spectrum. J. Antimicrob. Chemother. 51 (suppl. 2), ii9–ii16 (2003). 3. E. A. Weinstein, A. A. Ordonez, V. P. DeMarco, A. M. Murawski, S. Pokkali, E. M. MacDonald, M. Klunk, R. C. Mease, M. G. Pomper, S. K. Jain, Imaging Enterobacteriaceae infection in vivo with 18F-fluorodeoxysorbitol positron emission tomography. Sci. Transl. Med. 6, 259ra146 (2014).
4. M. L. Wilson, W. Winn, Laboratory diagnosis of bone, joint, soft-tissue, and skin infections. Clin. Infect. Dis. 46, 453–457 (2008). 5. A. W. J. M. Glaudemans, E. F. J. de Vries, F. Galli, R. A. J. O. Dierckx, R. H. J. A. Slart, A. Signore, The use of 18F-FDGPET/CT for diagnosis and treatment monitoring of inflammatory and infectious diseases. Clin. Dev. Immunol. 2013, 623036 (2013). 6. G. Gowrishankar, M. Namavari, E. B. Jouannot, A. Hoehne, R. Reeves, J. Hardy, S. S. Gambhir, Investigation of 6-[18F]fluoromaltose as a novel PET tracer for imaging bacterial infection. PLOS One 9, e107951 (2014). 7. X. Ning, W. Seo, S. Lee, K. Takemiya, M. Rafi, X. Feng, D. Weiss, X. Wang, L. Williams, V. M. Camp, M. Eugene, W. R. Taylor, M. Goodman, N. Murthy, Fluorine-18 labeled maltohexaose images bacterial infections by PET. Angew. Chem. Int. Ed. 10.1002/anie.201408533R1 (2014). 8. X. Ning, S. Lee, Z. Wang, D. Kim, B. Stubblefield, E. Gilbert,
N. Murthy, Maltodextrin-based imaging probes detect bacteria in vivo with high sensitivity and specificity. Nat. Mater. 10, 602–607 (2011). 9. K. B. Heller, E. C. Lin, T. H. Wilson, Substrate specificity and transport properties of the glycerol facilitator of Escherichia coli. J. Bacteriol. 144, 274–278 (1980). 10. Z. B. Li, Z. Wu, Q. Cao, D. W. Dick, J. R. Tseng, S. S. Gambhir, X. Chen, The synthesis of 18F-FDS and its potential application in molecular imaging. Mol. Imaging Biol. 10, 92–98 (2008). Competing interests: N.M. is an equity holder in Microbial Imaging, a company focused on using maltodextrins to target bacterial infections. 10.1126/scitranslmed.3010746 Citation: X. Wang, N. Murthy, Bacterial imaging comes of age. Sci. Transl. Med. 6, 259fs43 (2014).
Downloaded from stm.sciencemag.org on April 28, 2015
this issue of Science Translational Medicine, and the other two recent publications, suggest that a new chapter in bacterial imaging has begun.
www.ScienceTranslationalMedicine.org 22 October 2014 Vol 6 Issue 259 259fs43
3
