• Discitis
• Spinal epidural abscess
• Spinal infections
• Spondylitis
• Spondylodiscitis
• Vertebral osteomyelitis

• Humans
• Osteomyelitis/diagnosis
• Osteomyelitis/microbiology
• Osteomyelitis/drug therapy
• Osteomyelitis/therapy
• Anti-Bacterial Agents/therapeutic use
• Discitis/microbiology
• Discitis/diagnosis
• Spine/microbiology
• Spine/pathology
• Spinal Diseases/diagnosis
• Spinal Diseases/microbiology
• Spinal Diseases/therapy

• PET
• immunoPET
• invasive fungal infection
• radionuclide imaging
• siderophores

• Humans
• Positron-Emission Tomography/methods
• Mycoses/diagnostic imaging
• Antifungal Agents/therapeutic use
• Tomography, X-Ray Computed
• Invasive Fungal Infections
• Antibodies, Fungal

• ZIA CL090055 Intramural NIH HHS
• National Institutes of Health
• Czech Ministry of Education, Youth, and Sports
• European Union
• European Regional Development Fund
• Werner Siemens Foundation

• antifungal
• azole
• clotrimazole
• complexes
• fluconazole
• ketoconazole
• metal
• miconazole
• repurposing

• Computed Tomography
• FUO
• Fungal Infection
• Positron Emission Tomography

• Pharmacokinetics
• SPECT/CT
• host defence peptide
• isotope
• nuclear imaging
• radiotracer

• d-amino acid
• fungal infection
• glutamine
• metabolic imaging
• positron emission tomography

• Animals
• Candida albicans
• Glutamine/chemistry
• Invasive Fungal Infections
• Mammals
• Mice
• Mycoses
• Positron-Emission Tomography

• T32 HL134613 NHLBI NIH HHS

Imaging is needed for the diagnosis of bone and joint infections, determining the severity and extent of disease, planning biopsy, and monitoring the response to treatment. Some radiological features are pathognomonic of bone and joint infections for each modality used. However, imaging diagnosis of these infections is challenging because of several overlaps with non-infectious etiologies. Interventional radiology is generally needed to verify the diagnosis and to identify the microorganism involved in the infectious process through imaging-guided biopsy. This narrative review aims to summarize the radiological features of the commonest orthopedic infections, the indications and the limits of different modalities in the diagnostic strategy as well as to outline recent findings that may facilitate diagnosis.

• bone infections
• diagnosis
• imaging
• prosthesis infections

• HIV
• [18F]FDG PET/CT
• immunosuppression
• invasive fungal disease
• radionuclide imaging

• Antimicrobials
• Biodistribution
• CT
• Fluorescence
• MRI
• Mass spectrometry
• PET
• Pharmacokinetics
• Raman
• SPECT

• Animals
• Anti-Infective Agents/pharmacokinetics
• Diagnostic Imaging
• Fluorescence
• Humans
• Tissue Distribution

The human response to invading fungi includes a series of events that detect, kill, or clear the fungi. If the metabolic host response is unable to eliminate the fungi, an infection ensues. Some of the host response’s metabolic events to fungi can be imaged with molecules labelled with radionuclides. Several important clinical applications have been found with radiolabelled biomolecules of inflammation. ¹⁸F-fluorodeoxyglucose is the tracer that has been most widely investigated in the host defence of fungi. This tracer has added value in the early detection of infection, in staging and visualising dissemination of infection, and in monitoring antifungal treatment. Radiolabelled antimicrobial peptides showed promising results, but large prospective studies in fungal infection are lacking. Other tracers have also been used in imaging events of the host response, such as the migration of white blood cells at sites of infection, nutritional immunity in iron metabolism, and radiolabelled monoclonal antibodies. Many tracers are still at the preclinical stage. Some tracers require further studies before translation into clinical use. The application of therapeutic radionuclides offers a very promising clinical application of these tracers in managing drug-resistant fungi.

• PET
• SPECT
• fungi
• host defence
• inflammation
• invasive fungal infections
• radionuclides

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of immunocompromised humans, caused by the opportunistic fungal pathogen Aspergillus fumigatus. Inadequacies in current diagnostic procedures mean that early diagnosis of the disease, critical to patient survival, remains a major clinical challenge, and is leading to the empiric use of antifungal drugs and emergence of azole resistance. A non-invasive procedure that allows both unambiguous detection of IPA and its response to azole treatment is therefore needed. Here, we show that a humanised Aspergillus-specific monoclonal antibody, dual labelled with a radionuclide and fluorophore, can be used in immunoPET/MRI in vivo in a neutropenic mouse model and 3D light sheet fluorescence microscopy ex vivo in the infected mouse lungs to quantify early A. fumigatus lung infections and to monitor the efficacy of azole therapy. Our antibody-guided approach reveals that early drug intervention is critical to prevent complete invasion of the lungs by the fungus, and demonstrates the power of molecular imaging as a non-invasive procedure for tracking IPA in vivo.

Invasive pulmonary aspergillosis is a life-threatening fungal lung disease devoid of specific rapid diagnosis and with limited therapeutic options. Here, the authors show how state-of-the-art imaging approaches can enable specific diagnosis and therapy monitoring of this infection.

Invasive pulmonary aspergillosis (IPA) is a life-threatening infection of immunocompromised patients with Aspergillus fumigatus, a ubiquitous environmental mould. While there are numerous functioning antifungal therapies, their high cost, substantial side effects and fear of overt resistance development preclude permanent prophylactic medication of risk-patients. Hence, a fast and definitive diagnosis of IPA is desirable, to quickly identify those patients that really require aggressive antimycotic treatment and to follow the course of the therapeutic intervention. However, despite decades of research into this issue, such a diagnostic procedure is still not available. Here, we discuss the array of currently available methods for IPA detection and their limits. We then show that molecular imaging using positron emission tomography (PET) combined with morphological computed tomography or magnetic imaging is highly promising to become a future non-invasive approach for IPA diagnosis and therapy monitoring, albeit still requiring thorough validation and relying on further acceptance and dissemination of the approach. Thereby, our approach using the A. fumigatus-specific humanized monoclonal antibody hJF5 labelled with ⁶⁴Cu as PET-tracer has proven highly effective in pre-clinical models and hence bears high potential for human application.

• Aspergillus fumigatus
• aspergillosis
• imaging
• immunoPET
• invasive pulmonary aspergillosis
• positron emission tomography
• radiolabel
• siderophores

• MR/N006364/2 Medical Research Council

Background: Opportunistic fungal infections are increasingly common, with Candida albicans being the most common etiological agent; however, in recent years, episodes of candidiasis caused by non-albicansCandida species have emerged. Plants belonging to the Lauraceae family have shown remarkable antifungal effects. This study assessed the anti-Candida activity of Ocotea glomerata extracts and fractions, time of death and the synergistic effects with conventional antifungals. The possible mechanism of action was also addressed. Methods: Minimal inhibitory concentrations (MIC) were determined by broth microdilution technique, and the mechanism of action was assessed by ergosterol, sorbitol, cell viability, reactive oxygen species (ROS) generation and phosphatidylserine externalization tests. Results: All the tested extracts evidenced antifungal activity, but the methanol extract was revealed to be the most effective (MIC = 3.12 μg/mL) on C. krusei. The combination of methanol extract with ketoconazole and fluconazole revealed a synergistic effect for C. krusei and C. albicans, respectively. Fractions 1 and 5 obtained from the methanol extract had fungicidal activity, mainly against C. krusei. Methanol extract did not reveal effects by ergosterol and sorbitol assays; however, it led to an increase in intracellular ROS levels, decreased cell viability, and consequently, cell death. Conclusion: O. glomerata methanol extract may be viewed as a rich source of biomolecules with antifungal activity against Candida spp.

• Ocotea glomerata
• anti-candida activity
• mechanism of action
• natural products

• 99mTc-radiolabeling
• Infection imaging
• Inflammation imaging
• Levofloxacin
• Micelles

• abscess
• instrumentation
• spine
• spondylitis
• spondylodiscitis

• SPECT
• bacterial infection
• cell-tracking
• fluorescence
• multimodal
• ubiquicidin

• Animals
• Carbocyanines/chemistry
• Humans
• Mice
• Molecular Imaging
• Organotechnetium Compounds/administration & dosage
• Organotechnetium Compounds/chemistry
• Peptide Fragments/administration & dosage
• Peptide Fragments/chemistry
• Staphylococcal Infections/diagnostic imaging
• Staphylococcus aureus/growth & development
• Staphylococcus aureus/pathogenicity
• Thigh/diagnostic imaging
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon
• Urine/chemistry
• Urine/microbiology

• antibacterial
• gold nanorods
• molecular imaging
• photoacoustic
• silver nanoparticles

• Animals
• Anti-Bacterial Agents/chemistry
• Anti-Bacterial Agents/pharmacology
• Cell Line, Tumor
• Escherichia coli Infections/diagnostic imaging
• Escherichia coli Infections/drug therapy
• Gold/chemistry
• Gold/pharmacology
• Humans
• Male
• Metal Nanoparticles/chemistry
• Methicillin-Resistant Staphylococcus aureus/drug effects
• Mice
• Microbial Sensitivity Tests
• Particle Size
• Photoacoustic Techniques
• Silver/chemistry
• Silver/pharmacology
• Staphylococcal Infections/diagnostic imaging
• Staphylococcal Infections/drug therapy
• Surface Properties
• Wound Healing/drug effects

• DP2 HL137187 NHLBI NIH HHS
• R00 HL117048 NHLBI NIH HHS
• S10 OD021821 NIH HHS
• S10 OD023555 NIH HHS

• immunoPET-MRI
• invasive pulmonary aspergillosis
• magnetic resonance imaging
• monoclonal antibody (mAb)
• positron emission tomography

• Humans
• Infections/blood
• Infections/diagnostic imaging
• Leukocytes/metabolism
• Molecular Imaging/methods
• Radiopharmaceuticals

• R01 CA157372 NCI NIH HHS

Invasive aspergillosis has been studied in laboratory by the means of plethora of distinct animal models. They were developed to address pathophysiology, therapy, diagnosis, or miscellaneous other concerns associated. However, there are great discrepancies regarding all the experimental variables of animal models, and a thorough focus on them is needed. This systematic review completed a comprehensive bibliographic analysis specifically-based on the technical features of rodent models infected with Aspergillus fumigatus. Out the 800 articles reviewed, it was shown that mice remained the preferred model (85.8% of the referenced reports), above rats (10.8%), and guinea pigs (3.8%). Three quarters of the models involved immunocompromised status, mainly by steroids (44.4%) and/or alkylating drugs (42.9%), but only 27.7% were reported to receive antibiotic prophylaxis to prevent from bacterial infection. Injection of spores (30.0%) and inhalation/deposition into respiratory airways (66.9%) were the most used routes for experimental inoculation. Overall, more than 230 distinct A. fumigatus strains were used in models. Of all the published studies, 18.4% did not mention usage of any diagnostic tool, like histopathology or mycological culture, to control correct implementation of the disease and to measure outcome. In light of these findings, a consensus discussion should be engaged to establish a minimum standardization, although this may not be consistently suitable for addressing all the specific aspects of invasive aspergillosis.

• Aspergillus fumigatus
• experimental infection
• invasive aspergillosis
• mice
• rodent models

^99mTc-labeled antibiotics, antifungal drugs, antimicrobial peptides and COX-2 inhibitors are comprehensively reviewed.

Over the last forty years, a small group of commercial radiopharmaceuticals have found their way into routine medical use, for the diagnostic imaging of patients with infection or inflammation. These molecular radiotracers usually participate in the immune response to an antigen, by tagging leukocytes or other molecules/cells that are endogenous to the process. Currently there is an advancing effort by researchers in the preclinical domain to design and develop new agents for this application. This review discusses radiopharmaceuticals used in the nuclear medicine clinic today, as well as those potential radiotracers that exploit an organism's defence mechanisms to an infectious or inflammatory event.

With the rise in antibiotic-resistant infections, noninvasive sensing of infectious diseases is increasingly important. Optical imaging, while safer and simpler, is less developed than other modalities like radioimaging; due to low availability of target-specific molecular probes. Here, we report carbon nanotubes (SWNTs) as bacterial probes for fluorescence imaging of pathogenic infections. We demonstrate that SWNTs functionalized using M13 bacteriophage (M13-SWNT) can distinguish between F'-positive and F'-negative bacterial strains. Moreover, through one-step modification, we attach an anti-bacterial antibody on M13-SWNT, making it easily tunable for sensing specific F’-negative bacteria. We illustrate detection of Staphylococcus aureus intramuscular infections, with ~3.4× enhancement in fluorescence intensity over background. SWNT imaging presents lower signal spread ~0.08×, and higher signal amplification ~1.4×, compared to conventional dyes. We show the probe offers greater ~5.7× enhancement in imaging of S. aureus infective endocarditis. These biologically-functionalized, aqueous-dispersed, actively-targeted, modularly-tunable SWNT probes offer new avenues for exploration of deeply-buried infections.

• M13 bacteriophage
• bacterial infections
• fluorescent dye
• optical imaging

• Animals
• Bacteria/virology
• Bacterial Infections/diagnosis
• Bacterial Infections/virology
• Bacteriophage M13/metabolism
• Bacteriophage M13/physiology
• Female
• Fluorescent Dyes/metabolism
• Mice
• Molecular Imaging/methods

• P30 CA014051 NCI NIH HHS
• U54 CA151884 NCI NIH HHS
• 5-U54-CA151884-03 NCI NIH HHS

Soon after the introduction of the modern prosthetic joint, it was recognized that radionuclide imaging provides useful information about these devices. The bone scan was used extensively to identify causes of prosthetic joint failure. It became apparent, however, that although sensitive, regardless of how the images were analyzed or how it was performed, the test was not specific and could not distinguish among the causes of prosthetic failure. Advances in anatomic imaging, notably cross sectional modalities, have facilitated the diagnosis of many, if not most, causes of prosthetic failure, with the important exception of infection. This has led to a shift in the diagnostic paradigm, in which nuclear medicine investigations increasingly have focused on diagnosing infection. The recognition that bone scintigraphy could not reliably diagnose infection led to the development of combined studies, first bone/gallium and subsequently leukocyte/bone and leukocyte/marrow imaging. Labeled leukocyte imaging, combined with bone marrow imaging is the most accurate (about 90%) imaging test for diagnosing joint arthroplasty infection. Its value not withstanding, there are significant disadvantages to this test. In-vivo techniques for labeling leukocytes, using antigranulocyte antibodies have been explored, but have their own limitations and the results have been inconsistent. Fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET) has been extensively investigated for more than a decade but its role in diagnosing the infected prosthesis has yet to be established. Antimicrobial peptides bind to bacterial cell membranes and are infection specific. Data suggest that these agents may be useful for diagnosing prosthetic joint infection, but large scale studies have yet to be undertaken. Although for many years nuclear medicine has focused on diagnosing prosthetic joint infection, the advent of hybrid imaging with single-photon emission computed tomography(SPECT)/electronic computer X-ray tomography technique (CT) and the availability of fluorine-18 fluoride PET suggests that the diagnostic paradigm may be shifting again. By providing the anatomic information lacking in conventional radionuclide studies, there is renewed interest in bone scintigraphy, performed as a SPECT/CT procedure, for detecting joint instability, mechanical loosening and component malpositioning. Fluoride-PET may provide new insights into periprosthetic bone metabolism. The objective of this manuscript is to provide a comprehensive review of the evolution of nuclear medicine imaging of joint replacements.

• Bone scintigraphy
• Positron emission tomography
• ¹⁸F-fluorodeoxyglucose
• F-18
• Fluoride-positron emission tomography
• Gallium
• Infection
• Labeled leukocytes
• Prosthetic joint

Molecular imaging with single photon- and positron-emitting tracers plays an important role in the evaluation of inflammation and infection. Although supplanted by labeled leukocyte imaging for most indications, gallium-67 remains useful for opportunistic infections, pulmonary inflammation and interstitial nephritis and, when [¹⁸F]FDG is not available, spinal infection and fever of unknown origin. In vitro labeled leukocyte imaging is the radionuclide procedure of choice for most infections in immunocompetent patients. When performed for musculoskeletal infection, complementary bone marrow imaging usually is necessary. Recent data suggest that dual time point imaging might be an alternative to marrow imaging. Several methods of labeling leukocytes in vivo, with agents including antigranulocyte antibodies and antibody fragments, peptides and cytokines, have been investigated, with variable results. These agents are not widely available and none of them are available in the USA. Radiolabeled antibiotics have been investigated as “infection-specific” tracers, but the results to date have been disappointing. Conversely, radiolabeled antimicrobial peptides do hold promise as infection-specific tracers. The use of positron-emitting tracers for diagnosing inflammation and infection has generated considerable interest. [¹⁸F]FDG is useful in fever of unknown origin, spinal osteomyelitis, vasculitis and sarcoidosis. Other positron-emitting tracers that have been investigated include [¹⁸F]FDG-labeled leukocytes, copper-64-labeled leukocytes, gallium-68 citrate and iodine-124 FIAU. Although radiolabeled tracers are used primarily for diagnosis, they also offer objective biomarkers for assessing response to therapeutic interventions in inflammatory diseases. They could also potentially be used to target cells and molecules with specific receptor expression for histological characterization, select patients for receptor-targeted therapy and predict response to treatment.

• Antimicrobial peptides
• Biotin
• Gallium citrate
• Labeled leukocytes
• PET
• [18F]FDG

• Animals
• Gallium Radioisotopes
• Humans
• Infections/diagnostic imaging
• Inflammation/diagnostic imaging
• Positron-Emission Tomography/methods
• Radiopharmaceuticals/pharmacokinetics
• Rats
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon

• Animals
• Diagnostic Imaging/methods
• Humans
• Inflammation/diagnosis

• WT096497 Wellcome Trust
• G0901697 Medical Research Council
• G0601401 Medical Research Council
• WT094415 Wellcome Trust
• G0601481 Medical Research Council
• G0800969 Medical Research Council

Nuclear medicine imaging techniques offer whole body imaging for localization of number and site of infective foci inspite of limitation of spatial resolution. The innate human immune system contains a large member of important elements including antimicrobial peptides to combat any form of infection. However, development of antibiotics against bacteria progressed rapidly and gained popularity over antimicrobial peptides but even powerful antimicrobials failed to reduce morbidity and mortality due to emergence of mutant strains of bacteria resulting in antimicrobial resistance. Differentiation between infection and inflammation using radiolabeled compounds with nuclear medicine techniques has always been a dilemma which is still to be resolved. Starting from nonspecific tracers to specific radiolabeled tracers, the question is still unanswered. Specific radiolabeled tracers included antibiotics and antimicrobial peptides which bind directly to the bacteria for efficient localization with advanced nuclear medicine equipments. However, there are merits and demerits attributed to each. In the current paper, radiolabeled antibiotics and radiolabeled peptides for infection localization have been discussed starting with the background of primitive nonspecific tracers. Radiolabeled antimicrobial peptides have certain merits compared with labeled antibiotics which make them superior agents for localization of infective focus.

Invasive pulmonary aspergillosis is mainly caused by Aspergillus fumigatus, and is one of the major causes of morbidity and mortality in immunocompromised patients. The mortality associated with invasive pulmonary aspergillosis remains high, mainly due to the difficulties and limitations in diagnosis. We have shown that siderophores can be labelled with ⁶⁸Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising ⁶⁸Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE).

Siderophores were labelled with ⁶⁸Ga using acetate buffer. Log P, protein binding and stability values were determined. Uptake by A. fumigatus was studied in vitro in cultures with high and low iron loads. In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus. Static and dynamic μPET imaging was performed and correlated with CT images, and lung infection was evaluated ex vivo.

⁶⁸Ga-siderophores were labelled with high radiochemical purity and specific activity. ⁶⁸Ga-TAFC and ⁶⁸Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, ⁶⁸Ga-TAFC and ⁶⁸Ga-FOXE showed rapid renal excretion with high metabolic stability. In the rat infection model focal lung uptake was detected by μPET with both compounds and increased with severity of the infection, correlating with abnormal CT images.

⁶⁸Ga-TAFC and ⁶⁸Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus. Both compounds showed excellent pharmacokinetics, highly selective accumulation in infected lung tissue and good correlation with severity of disease in a rat infection model, which makes them promising agents for A. fumigatus infection imaging.

The online version of this article (doi:10.1007/s00259-012-2110-3) contains supplementary material, which is available to authorized users.

• Amino Acid Sequence
• Animals
• Anti-Infective Agents/administration & dosage
• Anti-Infective Agents/chemical synthesis
• Anti-Infective Agents/pharmacology
• Antimicrobial Cationic Peptides/administration & dosage
• Antimicrobial Cationic Peptides/chemical synthesis
• Antimicrobial Cationic Peptides/pharmacology
• Bacterial Infections/drug therapy
• Bacterial Infections/microbiology
• Candida/drug effects
• Chemistry Techniques, Synthetic
• Clinical Trials as Topic
• Drug Discovery
• Drug Evaluation
• Drug Resistance, Microbial
• Drug Synergism
• Humans
• Lactoferrin/administration & dosage
• Lactoferrin/chemistry
• Lactoferrin/pharmacology
• Methicillin-Resistant Staphylococcus aureus/drug effects
• Mice
• Molecular Sequence Data
• Mycoses/drug therapy
• Mycoses/microbiology
• Peptide Fragments/pharmacology