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M C IN O E P R Y V R A IG M H E T ® DI C A Q J NUCL MED MOL IMAGING 2006;50:147-52 Labeling of antibiotics for infection diagnosis A. BENITEZ, M. ROCA, J. MARTIN-COMIN The high impact of infection on daily clinical practice has promoted research into better and more accurate diagnostic and therapeutic methods. Localizing inflammation/infection with nuclear medicine techniques began over 40 years ago. Today, 67Ga-scintigraphy, 99m Tc-nanocolloid, 111 In and 99m Tc in vitro labeled leukocytes, and monoclonal antigranulocyte antibodies are widely available for this purpose. While these methods are useful for localizing inflammation, they cannot always differentiate septic from aseptic processes. The ideal properties of an agent for diagnosing infection include: high specificity, early diagnosis, rapid blood clearance, ease of preparation, low toxicity, biodistribution appropriate for the disease under study, absence of immunologic response and low cost. A novel approach to infection diagnosis is the use of radiolabelled antibiotics. Antibiotics localize in the infectious focus, where they are frequently taken up and metabolized by microorganisms. The majority of the various antibiotics studied so far are those of the quinolones group (ciprofloxacin, sparfloxacin, enrofloxacin, levofloxacin, norfloxacin and ofloxacin). More recently, the labeling of ceftizoxime, a semisynthetic third generation cephalosporin, has been reported. The relevant features of labeled antibiotics in research and/or clinical infection diagnosis are the focus of this article. K EY WORDS : Infection - Radionuclide imaging Technetium Tc 99m Sestamibi - Fluoroquinolones Ciprofloxacin - Sparfloxacin - Enrofloxacin Cephalosporins - Ceftizoxime. Address reprint requests to: Benitez A, S. Medicina Nuclear, Hospital Universitari de Bellvitge-IDIBELL, 08907 Hospitalet de Llobregat, Spain. E-mail: [email protected] Vol. 50 - No. 2 Service of Nuclear Medicine University Hospital of Bellvitge-IDIBELL Hospitalet de Llobregat, Spain T he early and accurate localization of infectious foci is a major challenge in contemporary nuclear medicine. Early and accurate diagnosis and localization allow prompt and successful treatment and decrease associated morbidity. Radiopharmaceuticals such as 67Ga-citrate, in vivo and in vitro labeled leukocytes, and labeled human immunoglobulins are sensitive for the diagnosis of inflammation. They are able to detect the physiological and biochemical changes that occur during the early phases of inflammation. However, none are capable of reliably differentiating sterile inflammation from septic infection. Nor are they are able to identify the presence of the microorganism causing the infection.1, 2 The ideal properties of an agent for diagnosing infection include: high specificity, early diagnosis, rapid blood clearance, ease of preparation, low toxicity, biodistribution appropriate to the disease under study, absence of immunologic response and low cost. Labeling with 99mTc is highly desirable, but other radionuclides may also be used. The labeling of antibiotics was introduced about a decade ago by Solanki et al. in their search for a better agent to diagnose infection.3 Theoretically, labeled antibiotics would be incorporated and metabolized by the bacteria present in the infectious focus and, assuming that the uptake is proportional to the number of microorganisms present, the measured radioactivity THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 147 BENITEZ LABELING OF ANTIBIOTICS FOR INFECTION DIAGNOSIS O O COOH H2C C H N S M C IN O E P R Y V R A IG M H E T ® DI C A F N N O HN N OH C O O CH Figure 1.—Chemical structure of ciprofloxacin. would accurately and specifically localize the infection. It is important to note that, as always in nuclear medicine diagnostic procedures, the amount of antibiotic used is minimal (tracer doses) and that the new radiopharmaceutical (the labeled antibiotic) does not have any therapeutic effect.4 Various antibiotics have been studied for this purpose, most of which are members of the quinolones class (ciprofloxacin, sparfloxacin, enrofloxacin, levofloxacin, norfloxacin and ofloxacin). Our group has recently introduced the labeling of ceftizoxime, a semisynthetic third generation cephalosporin. The relevant features of labeled antibiotics in research and/or clinical infection diagnosis are the focus of this article. Radiolabeling antibiotics with 99mTc The first antibiotic to be labeled with 99mTc for infectious foci localization was ciprofloxacin, a member of the fluoroquinolones group (Figure 1). The labeling of this antibiotic used formamidine sulphinic acid (FSA) in N2 atmosphere as a 99mTc-reductor agent and for the union of 99mTc-reduced-cyprofloxacin heating at 100º C for 10 min.3, 5 However, because the FSA was unstable and, as used in the formulation (2 mg ciprofloxacin + 400 mg FSA + 400 MBq 99mTc-pertechnectate), the labeling efficiency was inadequate (55±8%), the authors performed a purification step through a Sephadex DAE 81 column to retain nonreduced anionic free 99mTc. With this purification step, the labeling efficiency increased to 95% and the complex was stable for up to 8 h. The bacterial uptake of the labeled antibiotic in cultures containing Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli was 58.5%, 148 Figure 2.—Chemical structure of ceftizoxime. 50.2% and 43.9%, respectively. The uptake of 99mTcmethyl-diphosphonate used as a control was <2.5%. Similarly, cultures with dead bacteria showed a 99mTccyprofloxacin uptake <10%. After developing a new formulation, the same research group described another labeling method using stannous ion as the reducing agent.6 The new formulation was prepared in a kit formulation in 2 vials: the one containing the antibiotic solution (2 mg ciprofloxacin) and the other containing the lyophilized reducing agent (500 mg stannous tartrate). The labeling procedure was performed in 2 steps. In the first, 400 MBq of freshly eluted 99mTc-pertechnectate were added to the vial containing the reducing agent, and the antibiotic solution was added in the second step. After incubation for 15 min the radiopharmaceutical is ready for administration. The high labeling efficiency (>96%) obviates the purification step.7 This new method shortens preparation time and obviates the heating step. Later studies showed that the final radiopharmaceutical had in vitro and in vivo properties similar to the first one.8 Following these initial experiences, other fluoroquinolones have also been labeled with 99mTc: Levofloxacin,9 Sparfloxacin 10 and Enrofloxacin.11 All the procedures use stannous tartrate as the reducing agent, and a kit formulation is envisaged. Another antibiotic that has been radiolabelled is ceftizoxime, a third generation semisynthetic cephalosporin stable against beta-lactamase (Figure 2). Labeling is performed using sodium dithionite as the reducing agent in mildly alkaline pH (7.8-8). The 99mTc-ceftizoxime complex formation needs heating at THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING June 2006 LABELING OF ANTIBIOTICS FOR INFECTION DIAGNOSIS Although the labeled antibiotic is not taken up by neutrophils or macrophages present in the infectious focus, in vitro studies have demonstrated that while activated neutrophils and macrophages take up 99mTcciprofloxacin, the intracellular concentration diminishes with time.19 99mTc-ciprofloxacin scintigraphy may be more accurate than labeled leukocytes scintigraphy in the localization of bacterial infection.5, 13 It approaches the properties of an ideal tracer; does not require blood handling, is available in kit form, can be labeled with 99mTc, is easy and simple to prepare, and shelf stability is fairly long (8 h).6 As its efficacy does not depend on the presence of leukocytes, it can be used in leukopenic patients. Unlike labeled leukocytes, it is not taken up to any significant degree by the bone marrow; it seems to be more accurate than labeled leukocyte scintigraphy in localizing spinal infections.20 The accumulation of 99mTc-ciprofloxacin in the infectious focus does not appear to be influenced by previous antibiotic treatment. As published experience is limited, larger studies on patients with or without prior antibiotic treatment are necessary to confirm this point.17 In a multicenter trial on 500 patients with acute or chronic inflammation, infection and fever, the diagnosis of infection with the use of 99mTc-ciprofloxacin had a sensitivity 93%, a specificity of 86%, an accuracy of 90%, and the positive and negative predictive values were 92% and 86%, respectively.20 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 outline the lesion more accurately. It is interesting that in certain processes such as abscesses labeled leukocytes accumulate in the center of the lesion (where most bacteria are dead), while 99mTc-ciprofloxacin accumulates in the periphery (where most bacteria are alive and active). In other clinical settings such as inflammatory bowel disease, the labeled ciprofloxacin study is usually negative.17 Results are difficult to standardize. In the cited work, of the 7 patients with chronic inflammation the scan was negative in 4 (3 with inflammatory bowel disease and 1 with rheumatoid arthritis), and showed labeled antibiotic uptake in the remaining 3 (2 with inflammatory bowel disease and 1 with rheumatoid arthritis). Was this related to disease activity at examination? Was there leukocyte antibiotic uptake? While there are no a clear answers to these questions, it is important to note that the 4-h images normalized at 24 h. M C IN O E P R Y V R A IG M H E T ® DI C A 100 °C for 100 min. Under these conditions, labeling efficiency is 94.9±2.4% and in vitro stability is 6 h. Evaluated in agar diffusion plates containing E. coli, the biological activity of this new compound was 83% of the unbound antibiotic.12 BENITEZ Analysis of the main 99mTc-labelled antibiotics studied for the diagnosis of infection 99mTc-Ciprofloxacin 99mTc-Ciprofloxacin, a second generation broad spectrum quinolone, was introduced by Solanki et al. in 1993. Theirs was the first report of use of a labeled antibiotic for diagnosing rather than treating infection.3 Venjamuri et al. reported that use of the agent increased the diagnostic specificity of infection and could differentiate sterile from septic inflammation.13 MECHANISM OF ACTION Ciprofloxacin is active against Gram positive and Gram negative bacteria. It penetrates the cell through the membrane channels; once inside the cell, it binds to DNA gyrase (topoisomerase II), inhibiting its action.14 This mechanism applies to Gram negative bacteria, whereas in Gram positive bacteria the agent’s action is mediated by topoisomerase IV complexes.15, 16 Labeled ciprofloxacin is also active against ciprofloxacin-resistant bacteria.13, 17 BIODISTRIBUTION In the kidneys, bladder, liver and spleen, the early activity 99mTc-Ciprofloxacin diminishes in late images. Occasionally, gallbladder activity may also be seen accompanied by bowel activity. No uptake is seen in brain, normal bone, bone marrow or soft tissue.13, 18 CLINICAL EXPERIENCE The published results are controversial. Sonmezoglu et al. have applied 99mTc-ciprofloxacin scintigraphy to bone and orthopedic infection with a high accuracy, especially in chronic infection.6 Initial experiences, both in vitro and in vivo, showed that 99mTc-cyprofloxacin localizes at high concentrations in Gram negative and Gram positive induced abscesses but it does not localize in sterile inflammation or dead bacteria.5, 13, 17 Vol. 50 - No. 2 THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 149 BENITEZ LABELING OF ANTIBIOTICS FOR INFECTION DIAGNOSIS ciprofloxacin by the presence of an amino group in the C-5 position. This amino group seems to be responsible for Sparfloxacin’s greater antimicrobial power.27 It is excreted through liver and kidneys; maximal liver and kidney activities at 1, 4 and 24 h postinjection are: 5.7%, 6% and 4.6%, and 7%, 7.1% and 2.2%, respectively. M C IN O E P R Y V R A IG M H E T ® DI C A According to Larikka et al.,21 24 h imaging reduces the false positive rate and increases specificity from 68% to 95% in patients with total hip prosthesis. This early accumulation is due in part to the small size of the ciprofloxacin molecule that diffuses passively because of locally increased vascular permeability. Other false positive results have been described in patients with fibrous dysplasia, avascular necrosis,6 and inflammatory arthroplasties.17 Sonmezoglu et al., in a study using 99mTcciprofloxacin scanning of a group of patients with bone infection, reported 94% sensitivity, 83% specificity and 89% accuracy. In the authors’ opinion, the relative low specificity could have been the result of the low number of false negative (4 cases).6 Other authors have reported completely different findings. Sarda et al.7 found that the labeled antibiotic was unable to differentiate osteomyelitis and septic 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 et al. found low sensitivity (60%) in a group of patients with septic and degenerative arthropathies; the authors suggested the need to continue research into new more accurate agents. In a study on fever of unknown origin 25 the authors reported high specificity (100%) but low sensitivity (67%). Artiko et al.,26 in their study of abdominal and gastrointestinal infection, also found low sensitivity (79%) but high specificity (91%). These controversial results could be due to differences in the labeling procedure at the different centers using the same antibiotic or to differences in study populations or to many other reasons. The results from a multicenter trial now running in the United States and Canada will help to standardize the agent’s utility in clinical practice. 99mTc-Sparfloxacin Sparfloxacin, a member of a new generation of quinolones, is more powerful than ciprofloxacin. Like its predecessor, Sparfloxacin is active against Gram positive and Gram negative bacteria. MECHANISM OF ACTION AND BIODISTRIBUTION The action of Sparfloxacin is also mediated by its inhibitory action on DNA-gyrase but it differs from 150 CLINICAL EXPERIENCE Animal and in vitro studies with 99mTc-Sparfloxacin have shown preserved antimicrobial activity against S. aureus.10 Following the administration of 70 MBq of 99mTc-Sparfloxacin in normal rats, the maximal activity seen in the liver and kidney decreases with time. The lower hepatobiliary excretion of Sparfloxacin compared with ciprofloxacin (2.5% versus 6%) may be an important aid in the localization of abdominal infectious foci such as appendicitis. In inflamed/infected animals, both inflammatory and infectious foci show uptake in early images (2 h postinjection), whereas on the later images (4 h) only the infected focus shows uptake. The higher power of sparfloxacin versus ciprofloxacin provides a higher uptake of the labeled antibiotic in the infectious focus, for which higher sensitivity should be expected. A study to analyze the differences between sparfloxacin and ciprofloxacin is being conducted on patients with chronic osteomyelitis. 99mTc-Enrofloxacin Enrofloxacin, another antibiotic of the same Quinolone family with a chemical structure similar to ciprofloxacin, is active against Gram positive and Gram negative bacteria. In a very elegant study, Siaens et al.11 labeled this antibiotic with 99mTc and compared its efficacy with that of 99mTc-ciprofloxacin in a group of rats with intramuscular inflammation or infection: their results showed that none of the labeled quinolones were able to differentiate between sterile inflammation and infection. In the authors’ opinion, the labeled antibiotic did not show any specific binding to bacteria probably because of changes in the antibiotic structure during the labeling process. The scintigrams showed a moderate activity in the infectious foci at 1 h postinjection; however, the activity decreased progressively in the images at 4 h. This THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING June 2006 LABELING OF ANTIBIOTICS FOR INFECTION DIAGNOSIS mation/infection of different origin have shown 100% sensitivity, 83% specificity and 94%accuracy.32 Conclusions M C IN O E P R Y V R A IG M H E T ® DI C A nonspecific localization in the infectious focus probably results from inflammatory changes associated with infection such as local increase of permeability. In this study, there were no significant differences in the target/background ratio between inflammation and infection (S. aureus/Candida albicans). The only difference versus ciprofloxacin was the finding of higher liver, spleen and liver activity, which could have been related to the higher lipophilicity of the complex 99mTc-enrofloxacin.28 Other quinolones such as Levofloxacin 9 and Norfloxacin 29 have also been labeled with 99mTc, but experience with these agents is still very limited. BENITEZ Cephalosporins 99mTc-Ceftizoxime Ceftizoxime, a new third generation cephalosporin with beta-lactamase activity, binds to the bacterial membrane and inhibits the formation of the glycan peptide, inducing an inhibition in cellular wall buildup and eventually bacterial death.30 It is active against a broad spectrum of Gram negative and Gram positive bacteria. The agent can be labeled thanks to the presence of the electron donor groups in its chemical structure. ANIMAL AND CLINICAL EXPERIENCE In 1999, our group developed a method to label this third generation cephalosporin with 99mTc.12, 31 The basic labeling method takes about 30 min and requires heating at 100º C for 5 min. A kit presentation is being developed by our group. The labeled antibiotic retains 84% of the antibacterial activity of the original unlabelled agent. Following intravenous injection, 99mTc-ceftizoxime localizes in the liver, kidney and bladder; hepatobiliary excretion and bowel activity are also seen. Experimentally, it has been shown that 99mTc-ceftizoxime binds much more to live than to dead bacteria. In the same way, in rats with sterile induced abscess, 99mTc-uptake is lower than in rats with septic (E. coli) induced abscess. Moreover, activity decreases with time in sterile abscess, whereas in septic abscess it increases significantly in late images (30 min) versus late images (6 h). Initial studies on 23 patients with inflam- Vol. 50 - No. 2 99mTc-labelled antibiotics have opened a new, exciting field of research in infection diagnosis. Published results, though controversial, point to the possible utility of these novel agents in localizing infectious foci and the ability to distinguish such foci from sterile inflammation. Compared with agents under research or those recently approved, which are essentially neutrophil labeling procedures, labeled antibiotics represent a potentially significant advance in the diagnosis of infection. Because of their biodistribution and excretory pathways, the utility of these agents for diagnosing abdominal infection is probably somewhat limited. Most likely, labeled antibiotics will find the widest application in bone and orthopedic infections. References 1. Becker W. The contribution of nuclear medicine to the patient with infection. Eur J Nucl Med 1995;22:1195-211. 2. Becker W, Meller J. The role of nuclear medicine in infection and inflammation. Lancet Infect Dis 2001;1:326-33. 3. Solanki KK, Bomanji J, Siraj Q, Small M, Britton KE. 99mTc-infecton. A new class of radiopharmaceutical for imaging infection. J Nucl Med 1993;34 Suppl:119P. 4. DeNardo GL. When is too much too much and yet not enough? Alas, a plethora of opportunities but where’s the beef? J Nucl Med 2000;41:470-3. 5. Britton KE, Vinjamuri S, Hall AV, Solanki KK, Siraj Q, Bomanji J et al. Clinical evaluation of technetium-99m infecton for the localisation of bacterial infection. Eur J Nucl Med 1997;24:553-6. 6. Sonmezoglu K, Sonmezoglu M, Halac M, Akgun I, Turkmen C, Onsel C et al. Usefulness of 99mTc-ciprofloxacin (infecton) scan in diagnosis of chronic orthopedic infections: comparative study with 99mTc-HMPAO leukocyte scintigraphy. J Nucl Med 2001;42:56774. 7. Sarda L, Saleh-Mghir A, Peker C, Meulemans A, Crémieux AC, Le Guludec D. Evaluation of 99mTc-ciprofloxacin scintigraphy in a rabbit model of Staphilococcus aureux prosthetic joint infection. J Nucl Med 2002;43:239-45. 8. Kashyap R, Vinjamuri S, Hall AV, Das SS, Solanki KK, Britton KE. Imaging bacterial infection with a radiolabelled antibiotic. In: Cox PH, Buscombe JR, editors. The imaging of infection and inflammation. Amsterdam: Kluwer Academic Publishers; 1998.p.219-27. 9. Shimpi H.H, Nair N. 99mTc-Levofloxacin: An agent for infection imaging. Indian J Nucl Med 2003;18:16. 10. Singh AK, Verma J, Bhatnagar A, Ali A. Tc-99m labeled sparfloxacin: a specific infection imaging agent. World J Nucl Med 2003;:103-9. 11. 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M C IN O E P R Y V R A IG M H E T ® DI C A 14. LABELING OF ANTIBIOTICS FOR INFECTION DIAGNOSIS 15. 16. 17. 18. 19. 20. 21. 22. 152 25. 26. 27. 28. 29. 30. 31. 32. THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING June 2006