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Labeling of antibiotics for infection diagnosis
The high impact of infection on daily clinical prac-
tice has promoted resear
University Hospital of Bellvitge-IDIBELL oday, 67 MEDICA
ch into better and more accu-
rate diagnostic and therapeutic methods. Localizing
inflammation/infection with nuclear medicine tech-
niques began over 40 years ago. T AGa-scintig-

raphy, 99mTc-nanocolloid, 111In and 99mTc in vitro
labeled leukocytes, and monoclonal antigranulocyte
antibodies ar

e widely available for this purpose. While
The early and accurate localization of infectious foci is a major challenge in contemporary nuclear these methods are useful for localizing inflammation,
medicine. Early and accurate diagnosis and localiza- they cannot always differentiate septic from aseptic
tion allow prompt and successful treatment and processes. The ideal properties of an agent for diag-
decrease associated morbidity. Radiopharmaceuticals nosing infection include: high specificity, early diag-
nosis, rapid blood clearance, ease of preparation, low

such as 67Ga-citrate, in vivo and in vitro labeled leuko- toxicity, biodistribution appropriate for the disease
cytes, and labeled human immunoglobulins are sen- under study, absence of immunologic response and
sitive for the diagnosis of inflammation. They are able low cost. A novel approach to infection diagnosis is the
to detect the physiological and biochemical changes use of radiolabelled antibiotics. Antibiotics localize in
that occur during the early phases of inflammation.
the infectious focus, where they are frequently taken
However, none are capable of reliably differentiating up and metabolized by microorganisms. The majori-
sterile inflammation from septic infection. Nor are ty of the various antibiotics studied so far are those of
they are able to identify the presence of the microor- the quinolones group (ciprofloxacin, sparfloxacin,
enrofloxacin, levofloxacin, norfloxacin and ofloxacin).
The ideal properties of an agent for diagnosing More recently, the labeling of ceftizoxime, a semi-
synthetic third generation cephalosporin, has been

infection include: high specificity, early diagnosis, reported. The relevant features of labeled antibiotics
rapid blood clearance, ease of preparation, low tox- in research and/or clinical infection diagnosis are the
icity, biodistribution appropriate to the disease under COPYRIGHT
focus of this article.
study, absence of immunologic response and low KEY WORDS: Infection - Radionuclide imaging -
cost. Labeling with 99mTc is highly desirable, but oth- Technetium Tc 99m Sestamibi - Fluoroquinolones - Ciprofloxacin - Sparfloxacin - Enrofloxacin - The labeling of antibiotics was introduced about a decade ago by Solanki et al. in their search for a bet-ter agent to diagnose infection.3 Theoretically, labeledantibiotics would be incorporated and metabolized bythe bacteria present in the infectious focus and, assum- Address reprint requests to: Benitez A, S. Medicina Nuclear, Hospital ing that the uptake is proportional to the number of Universitari de Bellvitge-IDIBELL, 08907 Hospitalet de Llobregat, Spain.
E-mail: jmartincomin@csub.scs.es microorganisms present, the measured radioactivity THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LABELING OF ANTIBIOTICS FOR INFECTION DIAGNOSIS Figure 1.—Chemical structure of ciprofloxacin.
would accurately and specifically localize the infection.
Figure 2.—Chemical structure of ceftizoxime.
It is important to note that, as always in nuclear med-icine diagnostic procedures, the amount of antibiot-ic used is minimal (tracer doses) and that the new 50.2% and 43.9%, respectively. The uptake of 99mTc- methyl-diphosphonate used as a control was <2.5%.
Similarly, cultures with dead bacteria showed a 99mTc- maceutical (the labeled antibiotic) does not arious antibiotics have been studied for this purpose, most of which are members of the quinolones class After developing a new formulation, the same (ciprofloxacin, sparfloxacin, enrofloxacin, levofloxacin, research group described another labeling method norfloxacin and ofloxacin). Our group has recently using stannous ion as the reducing agent.6 The new introduced the labeling of ceftizoxime, a semisynthet- formulation was prepared in a kit formulation in 2 ic third generation cephalosporin. The relevant fea- vials: the one containing the antibiotic solution (2 mg tures of labeled antibiotics in research and/or clinical ciprofloxacin) and the other containing the lyophilized infection diagnosis are the focus of this article.
reducing agent (500 mg stannous tartrate). The label-ing procedure was performed in 2 steps. In the first,400 MBq of freshly eluted 99mTc-pertechnectate were Radiolabeling antibiotics with 99mTc
added to the vial containing the reducing agent, andthe antibiotic solution was added in the second step.
The first antibiotic to be labeled with 99mTc for infec- After incubation for 15 min the radiopharmaceutical tious foci localization was ciprofloxacin, a member is ready for administration. The high labeling effi- of the fluoroquinolones group (Figure 1). The label- ciency (>96%) obviates the purification step.7 This ing of this antibiotic used formamidine sulphinic acid new method shortens preparation time and obviates (FSA) in N2 atmosphere as a 99mTc-reductor agent and the heating step. Later studies showed that the final for the union of 99mTc-reduced-cyprofloxacin heating radiopharmaceutical had in vitro and in vivo proper- at 100º C for 10 min.3, 5 However, because the FSA was unstable and, as used in the formulation (2 mg Following these initial experiences, other fluoro- ciprofloxacin + 400 mg FSA + 400 MBq 99mTc-pertech- quinolones have also been labeled with 99mTc: COPYRIGHT
nectate), the labeling efficiency was inadequate Levofloxacin,9 Sparfloxacin 10 and Enrofloxacin.11 All (55±8%), the authors performed a purification step the procedures use stannous tartrate as the reducing through a Sephadex DAE 81 column to retain non- agent, and a kit formulation is envisaged.
reduced anionic free 99mTc. With this purification step, Another antibiotic that has been radiolabelled is the labeling efficiency increased to 95% and the com- ceftizoxime, a third generation semisynthetic cepha- losporin stable against beta-lactamase (Figure 2).
The bacterial uptake of the labeled antibiotic in Labeling is performed using sodium dithionite as the cultures containing Staphylococcus aureus, Pseudo- reducing agent in mildly alkaline pH (7.8-8). The monas aeruginosa and Escherichia coli was 58.5%, 99mTc-ceftizoxime complex formation needs heating at THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LABELING OF ANTIBIOTICS FOR INFECTION DIAGNOSIS 100 °C for 100 min. Under these conditions, labeling Although the labeled antibiotic is not taken up by efficiency is 94.9±2.4% and in vitro stability is 6 h.
neutrophils or macrophages present in the infectious Evaluated in agar diffusion plates containing E. coli, focus, in vitro studies have demonstrated that while the biological activity of this new compound was 83% activated neutrophils and macrophages take up 99mTc- ciprofloxacin, the intracellular concentration dimin-ishes with time.19 99mTc-ciprofloxacin scintigraphy may be more accu- Analysis of the main 99mTc-labelled antibiotics
rate than labeled leukocytes scintigraphy in the local- studied for the diagnosis of infection
ization of bacterial infection.5, 13 It approaches theproperties of an ideal tracer; does not require blood handling, is available in kit form, can be labeled with99mTc, is easy and simple to prepare, and shelf stabil- 99mTc-Ciprofloxacin, a second generation broad spec- ity is fairly long (8 h).6 As its efficacy does not depend trum quinolone, was introduced by Solanki et al. in on the presence of leukocytes, it can be used in 1993. Theirs was the first report of use of a labeled leukopenic patients. Unlike labeled leukocytes, it is not antibiotic for diagnosing rather than treating infection.3 taken up to any significant degree by the bone mar- Venjamuri et al. reported that use of the agent increased row; it seems to be more accurate than labeled leuko- the diagnostic specificity of infection and could differ- cyte scintigraphy in localizing spinal infections.20 entiate sterile from septic inflammation.13 The accumulation of 99mTc-ciprofloxacin in the infec- tious focus does not appear to be influenced by pre- vious antibiotic treatment. As published experience is limited, larger studies on patients with or without pri- Ciprofloxacin is active against Gram positive and or antibiotic treatment are necessary to confirm this Gram negative bacteria. It penetrates the cell through the membrane channels; once inside the cell, it binds In a multicenter trial on 500 patients with acute or to DNA gyrase (topoisomerase II), inhibiting its action.14 chronic inflammation, infection and fever, the diag- This mechanism applies to Gram negative bacteria, nosis of infection with the use of 99mTc-ciprofloxacin whereas in Gram positive bacteria the agent’s action is had a sensitivity 93%, a specificity of 86%, an accura- mediated by topoisomerase IV complexes.15, 16 Labeled cy of 90%, and the positive and negative predictive val- ciprofloxacin is also active against ciprofloxacin-resis- Scintigraphic images show a diffuse uptake in the infectious focus. The uptake can be seen as early as 1 h postadministration, but later images are a helpful aid to In the kidneys, bladder, liver and spleen, the early outline the lesion more accurately. It is interesting that in activity 99mTc-Ciprofloxacin diminishes in late images.
certain processes such as abscesses labeled leukocytes Occasionally, gallbladder activity may also be seen accumulate in the center of the lesion (where most bac- accompanied by bowel activity. No uptake is seen in teria are dead), while 99mTc-ciprofloxacin accumulates brain, normal bone, bone marrow or soft tissue.13, 18 in the periphery (where most bacteria are alive andactive). In other clinical settings such as inflammatorybowel disease, the labeled ciprofloxacin study is usual- ly negative.17 Results are difficult to standardize. In the cit- COPYRIGHT
The published results are controversial. Sonmezoglu ed work, of the 7 patients with chronic inflammation et al. have applied 99mTc-ciprofloxacin scintigraphy the scan was negative in 4 (3 with inflammatory bowel to bone and orthopedic infection with a high accura- disease and 1 with rheumatoid arthritis), and showed labeled antibiotic uptake in the remaining 3 (2 with Initial experiences, both in vitro and in vivo, showed inflammatory bowel disease and 1 with rheumatoid that 99mTc-cyprofloxacin localizes at high concentra- arthritis). Was this related to disease activity at examina- tions in Gram negative and Gram positive induced tion? Was there leukocyte antibiotic uptake? While there abscesses but it does not localize in sterile inflamma- are no a clear answers to these questions, it is important to note that the 4-h images normalized at 24 h.
THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LABELING OF ANTIBIOTICS FOR INFECTION DIAGNOSIS According to Larikka et al.,21 24 h imaging reduces ciprofloxacin by the presence of an amino group in the the false positive rate and increases specificity from C-5 position. This amino group seems to be respon- 68% to 95% in patients with total hip prosthesis. This sible for Sparfloxacin’s greater antimicrobial power.27 early accumulation is due in part to the small size of It is excreted through liver and kidneys; maximal liv- the ciprofloxacin molecule that diffuses passively er and kidney activities at 1, 4 and 24 h postinjection because of locally increased vascular permeability.
are: 5.7%, 6% and 4.6%, and 7%, 7.1% and 2.2%, Other false positive results have been described in patients with fibrous dysplasia, avascular necrosis,6and inflammatory arthroplasties.17 Sonmezoglu et al., in a study using 99mTc- ciprofloxacin scanning of a group of patients with Animal and in vitro studies with 99mTc-Sparfloxacin bone infection, reported 94% sensitivity, 83% specificity have shown preserved antimicrobial activity against S.
and 89% accuracy. In the authors’ opinion, the rela- aureus.10 Following the administration of 70 MBq of99m tive low specificity could have been the result of the Tc-Sparfloxacin in normal rats, the maximal activ- ity seen in the liver and kidney decreases with time.
Other authors have reported completely different The lower hepatobiliary excretion of Sparfloxacin findings. Sarda et al.7 found that the labeled antibiot- compared with ciprofloxacin (2.5% versus 6%) may be ic was unable to differentiate osteomyelitis and sep- an important aid in the localization of abdominalinfectious foci such as appendicitis.
In inflamed/infected animals, both inflammatory and infectious foci show uptake in early images (2 h tic arthritis from other non-septic inflammations.
Similarly, a low specificity was found in an S. aureus prosthesis infection animal model using rabbits.7, 22, 23
In a report published in 2002,24 Britton Afound low postinjection), whereas on the later images (4 h) only
sensitivity (60%) in a group of patients with septic and degenerative arthropathies; the authors suggest- The higher power of sparfloxacin versus ed the need to continue research into new more accu- ciprofloxacin provides a higher uptake of the labeled antibiotic in the infectious focus, for which higher In a study on fever of unknown origin 25 the authors reported high specificity (100%) but low sensitivity A study to analyze the differences between (67%). Artiko et al.,26 in their study of abdominal and sparfloxacin and ciprofloxacin is being conducted on gastrointestinal infection, also found low sensitivity patients with chronic osteomyelitis.
These controversial results could be due to differ- ences in the labeling procedure at the different cen- Enrofloxacin, another antibiotic of the same ters using the same antibiotic or to differences in study Quinolone family with a chemical structure similar populations or to many other reasons. The results to ciprofloxacin, is active against Gram positive and from a multicenter trial now running in the United States and Canada will help to standardize the agent’s In a very elegant study, Siaens et al.11 labeled this antibiotic with 99mTc and compared its efficacy withthat of 99mTc-ciprofloxacin in a group of rats with intramuscular inflammation or infection: their results COPYRIGHT
floxacin, a member of a new generation of showed that none of the labeled quinolones were quinolones, is more powerful than ciprofloxacin. Like able to differentiate between sterile inflammation and its predecessor, Sparfloxacin is active against Gram infection. In the authors’ opinion, the labeled antibi- positive and Gram negative bacteria.
otic did not show any specific binding to bacteriaprobably because of changes in the antibiotic structureduring the labeling process.
The scintigrams showed a moderate activity in the The action of Sparfloxacin is also mediated by its infectious foci at 1 h postinjection; however, the activ- inhibitory action on DNA-gyrase but it differs from ity decreased progressively in the images at 4 h. This THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LABELING OF ANTIBIOTICS FOR INFECTION DIAGNOSIS nonspecific localization in the infectious focus prob- mation/infection of different origin have shown 100% ably results from inflammatory changes associated sensitivity, 83% specificity and 94%accuracy.32 with infection such as local increase of permeability.
In this study, there were no significant differences inthe target/background ratio between inflammation Conclusions
and infection (S. aureus/Candida albicans). The onlydifference versus ciprofloxacin was the finding of 99mTc-labelled antibiotics have opened a new, excit- higher liver, spleen and liver activity, which could ing field of research in infection diagnosis. Published have been related to the higher lipophilicity of the results, though controversial, point to the possible utility of these novel agents in localizing infectious Other quinolones such as Levofloxacin 9 and foci and the ability to distinguish such foci from ster- Norfloxacin 29 have also been labeled with 99mTc, but experience with these agents is still very limited.
Compared with agents under research or those recently approved, which are essentially neutrophillabeling procedures, labeled antibiotics represent a Cephalosporins
potentially significant advance in the diagnosis ofinfection. Because of their biodistribution and excre- tory pathways, the utility of these agents for diag- nosing abdominal infection is probably somewhat Ceftizoxime, a new third generation cephalosporin limited. Most likely, labeled antibiotics will find the with beta-lactamase activity, binds to the bacterial widest application in bone and orthopedic infections.
peptide, inducing an inhibition in cellular wall build-up and eventually bacterial death.30 It is active against References
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