Journal of Orthopaedic Surgery 2005:13(2):190-194
Technetium-99m ciprofloxacin imaging in the diagnosis of postsurgical bony infection and evaluation of the response to antibiotic therapy: A case report B Singh, BR Mittal, A Bhattacharya Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
A Aggarwal, ON Nagi Department of Orthopaedic Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
AK Singh Department of Radiopharmacy, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India
ABSTRACT The use of radiolabelled antibiotics is fast emerging as a promising diagnostic test for the detection of infective lesions, because of their specific binding to the bacterial component. Ciprofloxacin is a broadspectrum antibiotic that has been used as a radiolabelled antibiotic in both the diagnosis of infections in rabbits and in clinical trials on humans. The diagnosis of skeletal microbial infections remains a challenge, especially in orthopaedic patients with implants. We present a case report of a patient with undiagnosed and unrelenting pain in the lower third of the left leg, which had persisted for 6 months. A novel scintigraphy, which was developed in-house using a 99mTc ciprofloxacin single vial kit, was used for diagnosing the active bacterial infection. A 99mTc methylene diphosphonate bone scan was also performed to locate precisely the site of the lesion.
Gradually increasing concentrations of both the radiotracers confirmed the presence of active bacterial infection in the distal third of the left tibia. Follow-up scanning after antibiotic therapy showed the disappearance of the pooling of 99mTc ciprofloxacin, indicating a good response. Therefore, 99m Tc ciprofloxacin has good diagnostic and prognostic applications in deep-seated covert skeletal microbial infections. However, the persistence of a focal concentration detected by the 99m Tc methylene diphosphonate scan was attributed to the inflammatory and not the infective pathology. Key words: antibiotic prophylaxis; osteomyelitis; radionuclide imaging; technetium Tc 99m ciprofloxacin
INTRODUCTION Bacterial infections continue to be one of the major
Address correspondence and reprint requests to: Dr Baljinder Singh, Assistant Professor, Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India. E-mail:
[email protected]
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causes of morbidity and mortality in developing countries. The most reliable method for early diagnosis of an infection is the analysis of microbiological samples taken from the lesion. The procedure is usually invasive and may be difficult or even impossible to perform in many cases. On the other hand, conventional anatomical imaging modalities such as plain radiography, ultrasonography, and computed tomography are useful only after abscess formation, which is a later manifestation of the infection. Many scintigraphic imaging agents such as gallium-67, radiolabelled leukocytes, human immunoglobulin, dextran, and peptides have been reported to detect and localise the infectious lesions.1–4 Although these agents have been proved useful, they have some drawbacks primarily because of their inability to differentiate between inflammatory and infectious lesions. The use of radiolabelled antibiotics presents a promising approach for the precise diagnosis and detection of infectious lesions, because they specifically bind to the bacterial component, making it possible to differentiate between infectious and sterile lesions.5,6 This imaging modality relies on the physiological and biochemical changes triggered by the presence of bacteria at the site of the lesion. These changes manifest much earlier than the clinical symptoms and therefore allow an early detection of the bacterial infection. In the present study, ciprofloxacin (4fluoroquinolone) was labelled with technetium99m ( 99m Tc) as 99m Tc ciprofloxacin (Diagnobact; INMAS, DRDO, New Delhi, India) and was used to identify the cause of the postsurgical and longstanding pain in the lower limb of the patient. The details of the preparation, radiochemical purity, animal experimentation, and the clinical utility of this radio-pharmaceutical have been reported elsewhere. 6–8 Although, this technique has been previously reported, this is the first report of an inhouse–developed method using a single vial kit preparation of the Diagnobact in the diagnosis of infective osteomyelitis.
a
CASE REPORT In February 2003, a 35-year-old man was presented to the orthopaedic out-patient clinic of the Postgraduate Institute of Medical Education and Research with a pain in the anterior aspect of the lower third of the left leg for the past 6 months. He underwent a surgical screw fixation procedure at another hospital 2 years earlier for a closed oblique fracture of the distal third of the left tibia. On presentation, the lateral and
b
Figure 1 (a) Lateral and (b) anteroposterior radiographs of the left leg before antibiotic treatment showing no overt abnormality.
anteroposterior radiographs of the left leg were not indicative or suggestive of any infection (Fig. 1). The pain did not subside even after removal of the screws. At the time of the screw removal, the bone and periosteum looked apparently normal, and no implant loosening was observed; hence, no histopathological examination was indicated. A 3-phase bone scan was performed 12 weeks after the implant removal. The scan was performed using the dual-headed Gamma Camera (E-Cam; Siemens, Erlangen, Germany) following an intravenous injection of 740 MBq of technetium-99m methylene diphosphonate (99mTc MDP; BRIT, BARC, Mumbai, India). Immediately, after the 99mTc MDP injection, anterior and posterior images were acquired for one minute (vascular phase, 64x64 matrix, 2 sec/frame, 30 frames). Subsequently, blood pool and delayed bony images were acquired (256x256 matrix, 500 000 counts) at 5 minutes and 3 hours after the injection. An increased blood flow, soft tissue uptake, and bone concentration of 99mTc MDP was seen in the lower third of the left tibia, indicative of inflammatory processes (Fig. 2). Because 99mTc MDP bone scan is highly sensitive but not specific, a 99mTc labelled ciprofloxacin scan was performed about
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Figure 2 The Tc MDP scans before antibiotic treatment showing (a) increased soft tissue (blood pool image at 5 minutes) and (b) bony uptake (3 hours delayed image) of the radiotracer as indicated by the arrows.
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(b) 99m
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(b) 99m
Figure 3 The Tc ciprofloxacin scan before antibiotic treatment showing focal concentration of the radiotracer in (a) one-hour and (b) 6-hour delayed images as indicated by the arrows.
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(b) 99m
Figure 4 The Tc MDP scan after antibiotic treatment showing (a) increased soft tissue (blood pool image at 5 minutes) and (b) bony uptake (3 hours delayed image) of the radiotracer as indicated by the arrows.
Figure 5 The Tc ciprofloxacin scan after antibiotic treatment showing no focal concentration of radiotracer in (a) one-hour and (b) 6-hour delayed images.
one week after the 99mTc MDP scan in order to confirm the presence or absence of active bacterial infection. Static isotime images taken over 5 minutes were acquired in a 256x256 matrix at 5 minutes (blood pool) and 6 hours following an intravenous injection of 740 MBq of 99mTc ciprofloxacin. The concentration of the radiotracer gradually increased over 6 hours in the lower third of the left tibial shaft, which was indicative of an active bacterial infection (Fig. 3). Broad-spectrum antibiotic treatment using an amoxycillin and clavulanic acid combination (625 mg, 8 hourly) was administered for 4 weeks followed by cefuroxime axetil (500 mg, 12 hourly) for another 4 weeks. The patient showed a marked clinical improvement with regression of local pain and swelling. At 8 weeks after the antibiotic therapy, the follow-up bone scan (99mTc MDP) showed a sharp,
intense focal area of increased concentration of the 99mTc MDP in the affected region of the tibia in both the blood pool and delayed static images (Fig. 4). However, the follow-up 99mTc ciprofloxacin scan, after 9 weeks of antibiotic therapy, did not show a focal area of increased uptake of the radiopharmaceutical in the lower third of the left tibial shaft (Fig. 5), compared with the previous scans. The indications for the repeat follow-up scanning were to assess the effect of antibiotic therapy, to correlate with the clinical findings, and to assess the complete eradication of the infection. The follow-up 99mTc MDP scan was performed at week 8 and the Diagnobact scan was performed at week 9 after the 8-week antibiotic therapy. A minimum interval of 3 to 4 days is required between these 2 different scans.
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Results of haematological tests at presentation were: haemoglobin (156 g/l), total leukocyte count (6000/mm 3), differential leukocyte count (70N, 26L, 2M, 2E, 0B), and erythrocyte sedimentation rate (20 mm/h). The C-reactive protein result was negative. After antibiotic treatment, the corresponding values were: haemoglobin (143 g/l), total leukocyte count (6300/mm 3), differential leukocyte count (74N, 20L, 4M, 2E, 0B), and erythrocyte sedimentation rate (18 mm/h).
DISCUSSION Ciprofloxacin is a potent broad-spectrum antibiotic, which is active against most of the gram-positive and gram-negative bacteria. The therapeutic property of the drug has been exploited for diagnostic use. The complex formed by chelation of 99mTc with ciprofloxacin is strong as indicated by in vitro serum stability and in vivo biodistribution experiments.8 In this study, the authors indicated that 99mTc forms a dimer or tetramer with the ciprofloxacin, and the complex formed has a strong affinity with serum proteins.8 The in vitro and in vivo study results have shown satisfactory labelling of ciprofloxacin with 99mTc, which is stable for up to 24 hours,7,8 and has both hepatobiliary and renal routes of excretion. The 99m Tc ciprofloxacin (Infecton; Bayer, Newbury, UK) has recently been established as a new radiopharmaceutical for infection imaging. Infecton is supplied as a 2-phase kit formulation, whereas the Diagnobact formulation used in the present study is a single vial kit preparation. Yaper et al.9 reported that Infecton has a sensitivity of 85%, specificity of 92%, and accuracy of 88% in detecting orthopaedic infections compared with 78%, 100%, and 90% respectively for combined bone and gallium imaging. They concluded that although the 2 modalities show a similar clinical yield, the easy availability and the short investigation time of Infecton make it the better option for the detection of orthopaedic infections. In another study, Britton et al.10 reported an overall sensitivity of 85.4% and a specificity of 81.7% for detecting infective foci in orthopaedic infections using another Infecton imaging technique. In a recent study, Sarda et al.11 reported a high sensitivity of 100%, low specificity of 37%, and high negative predictive value for the detection of bone and joint infection using 99mTc ciprofloxacin scintigraphy. They concluded that the method did not discriminate between infected and aseptic osteoarticular diseases. However, in another experimental study using the single vial kit of 99mTc
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ciprofloxacin, we have shown that this preparation does not concentrate in sterile and fungal lesions in experimental models.6 The uptake of any radiotracer in an infected site during the initial phase of testing is non-specific, because most of the tracer is distributed in the lesion blood pool and the extracellular space.6 Radiotracers with an affinity for the specific target component within the lesion space show a gradual increase in uptake with time, whereas non-specific tracers show a gradual outflow.12 In our case, the pretreatment blood pool and serial static 99mTc ciprofloxacin images at up to 6 hours indicated a gradual rise in the focal concentration in the affected site. 99mTc ciprofloxacin is a specific infection-imaging agent because it specifically binds to gyrase on the bacterial DNA, 13 and this radiotracer shows a continuous rise in bacterial models. In keeping with the experimental observations, this case report also indicates the efficacy of this preparation in detecting the postsurgical bacterial infection in the bone. However, the postantibiotic therapy scanning shows no focal concentration of the radiolabelled ciprofloxacin, despite 99m Tc MDP still concentrating in the distal third of the left tibia. This observation is attributed to the bony inflammation, whereas the bacterial infection in the affected site has already been controlled with the antibiotic treatment. The infective nature of the involved bony site was confirmed on the 99m Tc ciprofloxacin scan by the gradual increase of the radioactive tracer in the lesion, compared with the background ratio taken for 24 hours after the intravenous injection of the radiopharmaceutical. However, in inflammatory lesions, this tracer will completely washout in 4 to 6 hours. This finding is based on the experience of the nuclear medicine experts with this infection-imaging agent. The follow-up 99mTc ciprofloxacin scan of this particular patient did not show any increase in the radiotracer concentration. Therefore, 99m Tcciprofloxacin imaging has both diagnostic and prognostic implications not only in this particular patient, but also for general bacterial infections. Therefore, our scan findings prove the potential of this radiopharmaceutical preparation to resolve the diagnostic dilemma of differentiating bacterially infected sites from inflammatory or sterile lesions, and its use in follow-up scanning to evaluate the treatment response. All the radiodiagnostic investigations, such as computed tomography and magnetic resonance imaging, although sensitive, are not specific for infectious lesions and are very expensive. Hence,
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these methods have limited diagnostic applications in such cases, especially in developing countries. We recommend using the above imaging procedure in all the undiagnosed and clinically suspicious symptomatic cases of infection of the calf, because it is highly specific, sensitive, and least expensive. This new imaging radiopharmaceutical preparation needs to be trialled in a large number of patients to prove its
effectiveness. ACKNOWLEDGEMENT The authors wish to thank the Director of the Institute of Nuclear Medicine and Allied Sciences for providing the Diagnobact kits to enable us to carry out this study.
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