99mTc-amoxicillin: A novel radiopharmaceutical for infection imaging

Syeda Kiran Shahzadi; Muhammad Abdul Qadir; Shahzad Shabnam; Muhammad Javed

doi:10.1016/j.arabjc.2015.04.003

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Review

12 (

); 2533-2539

doi:

10.1016/j.arabjc.2015.04.003

^99mTc-amoxicillin: A novel radiopharmaceutical for infection imaging

Syeda Kiran Shahzadi^{^a,⁎}, Muhammad Abdul Qadir^{^a}, Shahzad Shabnam^{^a}, Muhammad Javed^{^b}

a Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan

b Institute of Nuclear Medicine and Oncology, Lahore, Pakistan

⁎Corresponding author at: Institute of Chemistry, Quaid-e-Azam Campus, University of the Punjab, Lahore, Pakistan. kiran.syyed@gmail.com (Syeda Kiran Shahzadi)

Received: 2015-2-19, Accepted: 2015-4-8, Published: 2015-12-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Amoxicillin, a penicillin derivative was synthesized as ready-to-used single vial kit and radiolabeled with technetium-99m. Various trials have been carried out to optimize the concentration of stannous chloride, amoxicillin, pH and reaction time. Radiochemical purity, in vitro and in vivo stability, partition co-efficient, protein binding and biodistribution in rabbit infected with Streptococcus pneumoniae were studied. The biodistribution studies in rabbit showed that ^99mTc-amoxicillin started to accumulate in the infected area at 1-h postadministration. ^99mTc-amoxicillin may prove itself as potential novel radiopharmaceutical for imaging infections caused by many bacteria.

Keywords

99mTc-amoxicillin

Scintigraphy

Radiopharmaceutical

99mTc

Streptococcus pneumoniae

Infection imaging

Show Related Articles from PubMed

1 Introduction

In developing countries where the environment is not fully hygienic, microbial actions are causing several infectious diseases associated with morbidity. So the identification of infection site at primary stage of the disease is crucial for successful treatment. The risk factors of morbidity that were associated with infectious diseases sharply decreased after the development of radiopharmaceuticals (Naqvi et al., 2012).

Now there is a wide range of antimicrobial agents that are being radiolabeled. The first group includes radiolabeled antibiotics such as ¹⁸F or ^99mTc-ciprofloxacin (Britton et al., 2001; Hall et al., 1996; Sarda et al., 2002, 2003; Siaens et al., 2004; Langer et al., 2005 ), ^99mTc-sparfloxacin (Singh et al., 2003), ^99mTc-ceftizoxime (Martin-Comin et al., 2004; Gomes et al., 2005) and ¹⁸F-fleroxacin (Fischman et al., 1992). The second group of infection imaging agents is derived from human anti-microbial peptides/proteins that have affinity to bind to specific bacterial antigens (Lupetti et al., 2003a,b), e.g. peptides (derived from human lactoferrin) (Welling et al., 2001), ubiquicidin labeled with ^99mTc or ¹⁸F (Lupetti et al., 2003a,b; Nibbering et al., 1998; Meléndez-Alafort et al., 2004; Akhtar et al., 2004; Welling et al., 2000; Zijlstra et al., 2006 ) and ^99mTc-human neutrophil peptide 1–3 (Welling et al., 1999). The third group consists of vitamins and bacterial growth factors, such as vitamin H, a group B vitamin (biotin) labeled with ¹¹¹In (Lazzeri et al., 2008).

Use of radiolabeled antibiotics is rapidly becoming an auspicious diagnostic test for the detection of infectious lesions because of its specific binding to bacterial components (Singh and Bhatnagar, 2010). The first clinical application of ^99mTc-ciprofloxacin was performed by Vinjamuri et al. (1996) and the capacity of ^99mTc imaging was compared with radiolabeled WBCs imaging to assess the bacterial infection (Vinjamuri et al., 1996). Most other fluoroquinolone antibiotics, cephalosporin and some other antibacterial agents were radiolabeled and used for imaging bacterial infections with promising results. Penicillin has been found to be more effective in several types of intracellular infections, including those caused by Helicobacter, Streptococcus, Bacillus subtilis, Haemophilus, Enterococcus and Moraxella (Amoxicillin Susceptibility and Resistance Data Retrieved 20 July 2013).

Amoxicillin is the penicillin derivative that is being radiolabeled and studied as radiopharmaceutical in the presented work. The data obtained about the labeling of ^99mTc with amoxicillin and its in vivo study are preliminary. Extensive research is required to investigate more efficient labeling conditions to label amoxicillin with ^99mTc. Also, some systematic experimentation is required to study the complete profile of efficacy and pharmacokinetics of ^99mTc-amoxicillin against a variety of gram-negative and gram-positive bacteria.

The objective of presented study was to develop ^99mTc-amoxicillin into a single vial kit to identify bacterial infection in experimental model of Streptococcus pneumoniae induced infectious lesion in a rabbit.

2 Materials and methods

Amoxicillin was donated by Java pharmaceutical; Lahore, Pakistan. 0.22 μm filters from MS® Nylon Membrane Filters, USA were used. ^99mTc was eluted as ^99mTcO₄⁻ from ⁹⁹Mo/^99mTc generator, PINSTECH, Islamabad, Pakistan. Radioactivity measurements were performed using Well-type NaI(Tl) gamma(γ)counter. All chemicals that were used in the research were of analytical grade and were used without further purifications. Rabbits were obtained from animal house, INMOL, Pakistan. All animal experiments were performed after the approval of Animal Ethical Committee of the institute.

2.1

2.1 Labeling procedure

Optimization studies were performed to find out the best conditions for the labeling of amoxicillin with technetium. Labeling efficiency was analyzed by varying stannous chloride concentration from 25 to 300 μg, amoxicillin concentration from 0.5 to 3 mg, pH from 3 to 7 and reaction time from 5 to 60 min. All the tests were performed in triplicates (n = 3).

To formulate the amoxicillin kit, 2.0 mg amoxicillin, 2.0 mg gentisic acid, 20 mg d-mannitol and 3.0 mg d-Penicillamine (co-ligand) were dissolved in 1 ml distilled water under continuous stirring (Solution A). Then stannous chloride, 50 μg (1 ml) from a solution having 50 μg SnCl₂·2H₂O and 5 mg Sodium/Potassium pyrophosphate in 1 ml distilled water, was added drop by drop to solution A. The pH was set at 5 by 0.1 N NaOH/0.1 N HCl. Then the kit solution was filtered by a (0.22 μm) filter. All experiments were performed at room temperature (30 ± 2 °C). Kits of amoxicillin were prepared, lyophilized and stored at 4 °C. Kit’s preparation was performed under sterile conditions in a laminar flow hood at room temperature. Freshly eluted sodium pertechnetate (370 MBq) obtained from in-house pakgen^99mTc-generator, was added to freeze dried kits and incubated at room temperature.

2.2

2.2 Radiochemical analysis

Radiochemical analysis of ^99mTc-amoxicillin was performed by Instant thin layer chromatography and paper chromatography. Paper chromatography was employed to determine the percentage of free pertechnetate (^99mTcO₄⁻). A strip of Whatman 3 MM chromatographic paper was marked 1 cm from above and below side with lead pencil. A drop of sample kit was spotted on the Whatman paper using 25 gauge (1 ml) insulin syringe and was placed into a sample vial containing acetone as a mobile phase. After the solvent has reached the front line, strip was removed and dried. Strip was cut into two equal pieces and their radioactivity was measured using well-type NaI(Tl) gamma(γ)counter.

To determine the %age of reduced/hydrolyzed technetium (^99mTcO₂), ITLC was employed. A strip of ITLC (6 cm × 1 cm) was marked 1 cm above from bottom with lead pencil. A 25 gauge (1 ml) insulin syringe was used to spot the drop at the paper strip. After that, paper strip was placed in a sample vial containing saline (0.9% NaOH) as a mobile phase. After the solvent reached the front line, strip was removed and dried. The strip was cut into two equal pieces and radioactivity of each piece was measured by using well-type NaI(Tl) gamma(γ)counter.

Percentage of labeled complex is calculated by subtracting the sum of ^99mTcO₂ and ^99mTcO₄⁻ from hundred.

2.3

2.3 Stability tests

The stability ^99mTc-amoxicillin complex at room temperature was studied to detect any dissociation of the complex and to determine suitable time for the injection of complex to avoid formation of undesired product which resulted from radiolysis of labeled complex. This undesired radioactive product may accumulate in nontarget organs.

For this purpose, ^99mTc-amoxicillin was kept at room temperature for 1–6 h. Radiochemical purity was checked after each hour by paper chromatography and ITLC to find any significant loss in labeling efficiency.

In vitro stability of ^99mTc-amoxicillin complex in blood serum was also checked to detect any degradation of the complex by blood serum enzymes. For this purpose, 5 ml blood was taken and centrifuged at 3000 rpm for 10 min. Blood serum was separated from blood cells. 1.8 ml of serum was taken out in a sample vial and 0.2 ml of ^99mTc-amoxicillin kit was added in it. Sample vial was incubated at 37 °C. Radiochemical purity of the labeled kit was checked for different time intervals (1–6 h) by using paper chromatography and instant thin layer chromatography (ITLC).

2.4

2.4 Partition coefficient

In order to calculate partition coefficient, octanol/saline was used as organic and inorganic layer. Counts in 100 μl of both layers were calculated with well-type NaI(TI) γ-counter. Partition coefficient value is calculated by Eq. (1) (mean ± SD, n = 3).

(1)

Log P Value : Log (% in octanol / % in saline)

2.5

2.5 Protein binding

Protein binding of the labeled complex was measured by incubating it with fresh human blood for 1 h, placing it in a pre-set water bath (37 °C) for 10 min, centrifuging at 3000 rpm, including equal volume of 10% “Trichloroacetic acid” (TCA) and centrifuging again. Afterward both supernatant and residue were counted for radioactivity.

2.6

2.6 In vitro binding of ^99mTc-amoxicillin with bacteria

To study the binding assay of ^99mTc-amoxicillin with bacteria, in vitro studies were performed. Approximately 3 ml of bacterial culture (S. pneumoniae) was centrifuged for 10 min. Supernatant was separated from pellet and was poured into a sterile sample vial. Pellet was resuspended into 1.5 ml of acetic acid (0.2 M) and 1.5 ml of sodium phosphate buffer (0.2 M). 0.8 ml of resulting solution was taken into three different tubes and 0.1 ml of sodium phosphate buffer was added into each tube. 10 μg, 50 μg and 100 μg of ^99mTc-amoxicillin were added into each tube and incubated at 4 °C for 1 h. After incubation, all the tubes were centrifuged for 5 min. Supernatant was separated into a separate tube and pellet was suspended into 1 ml sodium phosphate buffer and was centrifuged for 5 min. Radioactivity measurements were taken separately for both supernatant and pellet by using well type gamma ray counter. Percent binding of given complex with bacteria was found by Eq. (2) as follows:

(2)

% Binding to Bacteria = Counts in Pellet / (Counts in Supernatant + Counts in Pellet) \times 100

2.7

2.7 Biodistribution

For normal biodistribution studies, 500 μl (74 MBq) of ^99mTc-amoxicillin was injected in the iliac vein of rabbit after valium (1.0 ml) anesthesia. Scintigraphic images were taken at 1 h and 2 h postinjection with Infinia dual head gamma camera.

For biodistribution study in infected rabbit, 1.0 ml suspension (3 × 10⁸ CFU/ml) of S. pneumoniae was injected in rabbit (thigh muscles). After the initiation of swelling at the infected site of rabbit, 500 μl (74 MBq) of ^99mTc-amoxicillin was injected. Scintigraphic images were taken at 1 h, 2 h and 24 h postinjection with Infinia dual head gamma camera.

3 Results and discussion

Various electron donor species are present in amoxicillin structure e.g. oxygen, nitrogen and sulfur (Fig. 1a). ^99mTc can interact and form complex with these electron donor atoms. Also, d-Penicillamine can provide additional electron donating atoms for transchelation. Although exact structure of ^99mTc-amoxicillin is unknown, proposed structure of this complex is given in Fig. 1b.

Proposed structure of 99mTc-amoxicillin complex.

Optimization of labeling conditions revealed that highest labeling efficiency was achieved when 50 μg stannous chloride, and 2 mg amoxicillin was labeled with sodium pertechnetate (370 MBq) at pH 5 and incubation time of 30 min. The reaction is favorable at little acidic pH but by shifting toward basic pH, labeling efficiency decreased. At these conditions, maximum labeling yield was >98%. In ITLC, saline was used as solvent, very small activity remained at origin corresponding to reduced ^99mTc. In paper chromatography, acetones were used as solvent, and small amount of the activity was moved which was belonged to free ^99mTcO₄⁻.

3.1

3.1 Effect of stannous chloride concentration

Stannous chloride is commonly used as reducing agent for the reduction of pertechnetate, which favors its chelation with amoxicillin. Fig. 2 illustrates the variation of labeling efficiency, free ^99mTcO₄⁻ and the reduced/hydrolyzed ^99mTcO₂ with changing concentration of reducing agent.

Effect of stannous chloride concentration on labeling yield of 99mTc-amoxicillin complex.

Stannous chloride concentration has strong effect on labeling yield, amount of free pertechnetate and colloidal form. With the increase in stannous chloride concentration, labeling yield was observed to increase with the corresponding decrease in percentage of free pertechnetate and colloidal form. At 50 μg, labeling efficiency was found to increase to about 98%. It was the lowest amount of stannous chloride that reduced the maximum amount of ^99mTcO₄⁻, hence offered maximum labeling yield. When the concentration of stannous chloride was increased above 300 μg, amount of colloidal form was observed to increase to a larger extent with corresponding decrease in labeling efficiency.

3.2

3.2 Effect of amoxicillin concentration

Concentration of amoxicillin was varied from 0.5 mg to 3 mg and labeling efficiency was checked at each concentration to optimize the minimum amount of amoxicillin that will give the maximum labeling. Fig. 3 clearly depicts the effect of amoxicillin concentration on labeling yield, amount of free ^99mTcO₄⁻ and reduced/hydrolyzed (^99mTcO₂) form. By increasing amoxicillin concentration, labeling yield was found to increase up to 2 mg of amoxicillin. By further increasing the amoxicillin amount, there was no significant increase in labeling yield or decrease in level of free ^99mTcO₄⁻ and reduced/hydrolyzed (^99mTcO₂) form. After addition of 2 mg concentration of amoxicillin, labeling yield and amount of free ^99mTcO₄⁻ and reduced/hydrolyzed (^99mTcO₂) form become almost constant. It depicted that 2 mg concentration of amoxicillin is best for maximum labeling yield.

Effect of amoxicillin concentration on labeling yield 99mTc-amoxicillin complex.

3.3

3.3 Effect of pH

Labeling yield was affected by changing pH of the reaction mixture. At low pH, labeling yield was poor. By increasing pH, labeling yield also increased till pH 5. After pH 5, labeling efficiency started decreasing with corresponding increase in amount of free ^99mTcO₄⁻ and reduced/hydrolyzed (^99mTcO₂) (Fig. 4).

Effect of pH of reaction mixture on labeling yield 99mTc-amoxicillin complex.

3.4

3.4 Effect of reaction time

Reaction time represents the minimum time required to label the complex. The maximum yield was achieved at 30 min. After 30 min, it reached to its saturation value i.e. by increasing time, labeling yield remained almost constant (Fig. 5).

Effect of reaction time on labeling yield 99mTc-amoxicillin complex.

3.5

3.5 Stability tests

In vitro stability tests at room temperature and in human serum at 37 °C showed stability for 6 h (Fig. 6). The complex showed no significant disintegration till 6 h. It means that there was no colloidal impurity and instability.

In vitro stability of 99mTc-amoxicillin complex at room temperature and in human serum at 37 °C.

3.6

3.6 Protein binding and partition co-efficient

^99mTc-amoxicillin complex showed high binding with proteins. Almost 76 ± 5% of ^99mTc-amoxicillin complex showed protein binding while 24 ± 5% of it remained unbound.

Partition coefficient test was conducted to find the nature of the complex i.e. it was either lipophilic or hydrophilic. High log P value showed that the ^99mTc-amoxicillin complex was highly lipophilic.

3.7

3.7 In vitro binding of ^99mTc-amoxicillin to bacteria

In vitro binding of ^99mTc-amoxicillin complex with S. pneumoniae showed that binding of ^99mTc-amoxicillin with bacteria was highly dependent on incubation time and concentration (Fig. 7).

In vitro binding of 99mTc-amoxicillin with Streptococcus pneumoniae.

After first hour of incubation, binding of ^99mTc-amoxicillin with S. pneumoniae was 3.5% at 100 μg concentration which was very low, but after 2 h, its binding was increased and was found to be 60% at 50 μg concentration.

3.8

3.8 Biodistribution

In normal biodistribution studies, at first hour radio-ligand was accumulated in the liver, and spleen but cleared rapidly after 2 h, so excretion is time dependent as shown in scintigraphic images (Fig. 8). Biodistribution in normal rabbit showed higher value of activity in kidney and bladder and it is suggested that ^99mTc-amoxicillin is excreted mainly through this pathway.

Biodistribution in normal rabbit at 1-h and 2-h postinjection of 99mTc-amoxicillin.

In-vivo binding with S. pneumoniae showed encouraging results (Fig. 9). Scintigraphic data also explained that 1 h postinjection is the minimum time suitable for scanning of infection.

Biodistribution in infected rabbit at 1-h, 2-h and 24-h postinjection of 99mTc-amoxicillin.

The excretion of the radioactivity from organs is fast and there was no accumulation in any organs and after 24 h some of its quantity was observed at infection site and urinary bladder (Table 1).

Table 1 Bio-distribution of ^99mTc-amoxicillin in Streptococcus pneumoniae infected rabbit (% ID/g ± SD, n = 3).

Organ	1 h	2 h	24 h
Thigh (target)	1.92 ± 0.08	2.24 ± 0.09	0.89 ± 0.06
Thigh (non-target)	0.54 ± 0.08	0.48 ± 0.01	0.39 ± 0.02
Kidneys (LT)	1.43 ± 1.10	1.57 ± 1.20	1.22 ± 1.23
Kidneys (RT)	2.06 ± 1.40	1.70 ± 1.23	1.44 ± 1.4
Liver	2.09 ± 1.21	1.83 ± 1.23	1.89 ± 1.26
Urinary bladder	52.11 ± 1.2	63.78 ± 1.24	63.82 ± 1.27

4 Conclusion

In present work amoxicillin kits were prepared, and radio-labeled with ^99mTc and labeling yield was (<95%). ^99mTc-amoxicillin complex was found to be stable at room temperature and also in human blood serum at 37 °C for 6 h. The radio-labeled kits showed good binding efficiency both in in vitro and in vivo studies against S. pneumoniae. The complex showed high uptake in infected thigh muscle within 1 h postinjection so it is suggested best suitable time for the imaging of infection. These promising characteristics of ^99mTc-amoxicillin make it a suitable candidate for imaging infection foci against a variety of bacteria.

Acknowledgments

Authors are very grateful to Mr. Irfan-Ullah Khan, Principal Scientist at INMOL Lahore for his fruitful discussion and Mr. Khalid Mehmod Senior Technician at INMOL Lahore for assisting in taking rabbit scans. Authors are also thankful to Director of INMOL for providing facilities for this research work.

References

Akhtar M.S., Iqbal J., Khan M.A., Irfanullah J., Jehangir M., Khan B., Haq I., Muhammad G., Nadeem M.A., Afzal M.S., Imran M.B., . ^99mTc-labeled antimicrobial peptide ubiquicidin (29–41) accumulates less in Escherichia coli infection than in Streptococcus pneumoniae infection. J. Nucl. Med.. 2004;45:849-856.
[Google Scholar]
Amoxicillin Susceptibility and Resistance Data (retrieved 20.07.13).
Britton K.E., Wareham D.W., Das S.S., Solanki K.K., Amaral H., Bhatnagar A., Katamihardja A.H.S., Malamitsi J., Moustafa H.M., Soroa V.E., Sundram F.X., Padhy A.K., . Imaging bacterial infection with ^99mTc-ciprofloxacin (Infecton) J. Clin. Pathol.. 2001;55:817-823.
[Google Scholar]
Fischman A.J., Livni E., Babich J., Alpert N.M., Liu Y.Y., Thom E., Cleeland R., Prosser B.L., Callahan R.J., Correia J.A., . Pharmacokinetics of 18F-labeled fleroxacin in rabbits with Escherichia coli infections, studied with positron emission tomography. Antimicrob. Agents Chemother.. 1992;36:2286-2292.
[Google Scholar]
Gomes B.V., Rabiller G., Iglesias F., Soroa V., Tubau F., Roca M., Martín-Comín J., . ^99mTc-ceftizoxime scintigraphy in normal rats and abscess induced rats. Rev. Esp. Med. Nucl.. 2005;24:312-318.
[Google Scholar]
Hall A.V., Solanki K.K., Vinjamuri S., Britton K.E., Das S.S., . Evaluation of the efficacy of ^99mTc-Infecton, a novel agent for detecting site of infection. J. Clin. Pathol.. 1996;51:215-219.
[Google Scholar]
Langer O., Brunner M., Zeitlinger M., Ziegler S., Müller U., Dobrozemsky G., Lackner E., Joukhadar C., Mitterhauser M., Wadsak W., Minar E., Dudczak R., Kletter K., Müller M., . In vitro and in vivo evaluation of [18F] ciprofloxacin for the imaging of bacterial infections with PET. Eur. J. Nucl. Med. Mol. Imag.. 2005;32:143-150.
[Google Scholar]
Lazzeri E., Erba P., Perri M., Tascini C., Doria R., Giorgetti J., Mariani G., . The scintigraphic imaging of vertebral osteomyelitis with ¹¹¹In-biotin. Spine. 2008;33:E198-E204.
[Google Scholar]
Lupetti A., Pauwels E.K.J., Nibbering P.H., Welling M.M., . ^99mTc-antimicrobial peptides: promising candidates for infection imaging. J. Nucl. Med.. 2003;47:238-245.
[Google Scholar]
Lupetti A., Welling M.M., Pauwels E.K., Nibbering P.H., . Radiolabelled antimicrobial peptides for infection detection. Lancet Infect. Dis.. 2003;3:223-229.
[Google Scholar]
Martin-Comin J., Soroa V., Rabiller G., Galli R., Cuesta L., Roca M., . Diagnosis of bone infection with 99mTc-ceftizoxime. Rev. Esp. Med. Nucl.. 2004;23:357.
[Google Scholar]
Meléndez-Alafort L., Rodrìguez-Cortés J., Ferro-Flores G., Murphy C.A., Herrera-Rodrìguez R., Martìnez-Duncker C., . Biokinetics of ^99mTc-UBI in humans. Nucl. Med. Biol.. 2004;31:373-379.
[Google Scholar]
Naqvi S.A.R., Ishfaq M.M., Khan Z.A., Nagra S.A., Bukhari I.H., Hussain A.I., Mahmood N., Shahzad S.A., Haque A., Bokhari T.H., . ^99mTc labeled levofloxacin as an infection imaging agent: a novel method for labeling levofloxacin using cysteine·HCl as co-ligand and in vivo study. Turk. J. Chem.. 2012;36:267-277.
[Google Scholar]
Nibbering P.H., Welling M., van den Broek P.J., Pauwels E.K.J., . Radiolabeled antimicrobial peptides for imaging of infection: a review. Nucl. Med. Commun.. 1998;19:1117-1121.
[Google Scholar]
Sarda L., Saleh-Mghir A., Peker C., Meulemans A., Crémieux A.C., Le Guludec D., . Evaluation of (99m)Tc-ciprofloxacin scintigraphy in a rabbit model of Streptococcus pneumoniae prosthetic joint infection. J. Nucl. Med.. 2002;43:239-245.
[Google Scholar]
Sarda L., Crémieux A.C., Lebellec Y., Meulemans A., Lebtahi R., Hayem G., Génin R., Delahaye N., Huten D., Le Guludec D., . Inability of 99mTc-ciprofloxacin scintigraphy to discriminate between septic and sterile osteoarticular diseases. J. Nucl. Med.. 2003;44:920-926.
[Google Scholar]
Siaens R.H., Rennen H.J., Boerman O.C., Dierckx R., Slegers G., . Synthesis and comparison of Tc-99m-enrofloxacin and Tc-99m-ciprofloxacin. J. Nucl. Med.. 2004;45:2088-2094.
[Google Scholar]
Singh N., Bhatnagar A., . Clinical evaluation of efficacy of ^99mTc ethambutol in tubercular lesion imaging. Tuberc. Res. Treat. Hind. Pub. Corp. 2010:1-9.
[Google Scholar]
Singh A.K., Verma J., Bhatnagar A., Ali A., . Tc-99m labeled sparfloxacin: a specific infection imaging agent. J. Nucl. Med.. 2003;2:103-109.
[Google Scholar]
Vinjamuri S.H., Hall A.V., Solanki K.K., Bomanji J., Siraj Q., Shaughnessy E., Das S.S., Britton K.E., . Comparison of ^99mTc Infection imaging with radiolabeled white-cell imaging in the evaluation of bacterial infection. Lancet. 1996;347:233-235.
[Google Scholar]
Welling M.M., Nibbering P.H., Paulusma-Annema A., Hiemstra P.S., Pauwels E.K., Calame W., . Imaging of bacterial infections with ^99mTc-labeled human neutrophil peptide-1. J. Nucl. Med.. 1999;40:2073-2080.
[Google Scholar]
Welling M.M., Paulusma-Annema A., Balter H.S., Pauwels E.K., Nibbering P.H., . Technetium-99m labeled antimicrobial peptides discriminate between bacterial infections and sterile inflammations. Eur. J. Nucl. Med.. 2000;27:292-301.
[Google Scholar]
Welling M.M., Lupetti A., Balter H.S., Lanzzeri S., Souto B., Rey A.M., Savio E.O., Paulusma-Annema A., Pauwels E.K., Nibbering P.H., . ^99mTc-labeled antimicrobial peptides for detection of bacterial and Candida albicans infections. J. Nucl. Med.. 2001;42:788-794.
[Google Scholar]
Zijlstra S., Gunawan J., Freytag C., Burchert W., . Synthesis and evaluation of fluorine-18 labeled compounds for imaging of bacterial infections with PET. Appl. Radiat. Isot.. 2006;64:802-807.
[Google Scholar]

Show Sections

[1] Akhtar M.S., Iqbal J., Khan M.A., Irfanullah J., Jehangir M., Khan B., Haq I., Muhammad G., Nadeem M.A., Afzal M.S., Imran M.B., . ^99mTc-labeled antimicrobial peptide ubiquicidin (29–41) accumulates less in Escherichia coli infection than in Streptococcus pneumoniae infection. J. Nucl. Med.. 2004;45:849-856.
[Google Scholar]

[2] Amoxicillin Susceptibility and Resistance Data (retrieved 20.07.13).

[3] Britton K.E., Wareham D.W., Das S.S., Solanki K.K., Amaral H., Bhatnagar A., Katamihardja A.H.S., Malamitsi J., Moustafa H.M., Soroa V.E., Sundram F.X., Padhy A.K., . Imaging bacterial infection with ^99mTc-ciprofloxacin (Infecton) J. Clin. Pathol.. 2001;55:817-823.
[Google Scholar]

[4] Fischman A.J., Livni E., Babich J., Alpert N.M., Liu Y.Y., Thom E., Cleeland R., Prosser B.L., Callahan R.J., Correia J.A., . Pharmacokinetics of 18F-labeled fleroxacin in rabbits with Escherichia coli infections, studied with positron emission tomography. Antimicrob. Agents Chemother.. 1992;36:2286-2292.
[Google Scholar]

[5] Gomes B.V., Rabiller G., Iglesias F., Soroa V., Tubau F., Roca M., Martín-Comín J., . ^99mTc-ceftizoxime scintigraphy in normal rats and abscess induced rats. Rev. Esp. Med. Nucl.. 2005;24:312-318.
[Google Scholar]

[6] Hall A.V., Solanki K.K., Vinjamuri S., Britton K.E., Das S.S., . Evaluation of the efficacy of ^99mTc-Infecton, a novel agent for detecting site of infection. J. Clin. Pathol.. 1996;51:215-219.
[Google Scholar]

[7] Langer O., Brunner M., Zeitlinger M., Ziegler S., Müller U., Dobrozemsky G., Lackner E., Joukhadar C., Mitterhauser M., Wadsak W., Minar E., Dudczak R., Kletter K., Müller M., . In vitro and in vivo evaluation of [18F] ciprofloxacin for the imaging of bacterial infections with PET. Eur. J. Nucl. Med. Mol. Imag.. 2005;32:143-150.
[Google Scholar]

[8] Lazzeri E., Erba P., Perri M., Tascini C., Doria R., Giorgetti J., Mariani G., . The scintigraphic imaging of vertebral osteomyelitis with ¹¹¹In-biotin. Spine. 2008;33:E198-E204.
[Google Scholar]

[9] Lupetti A., Pauwels E.K.J., Nibbering P.H., Welling M.M., . ^99mTc-antimicrobial peptides: promising candidates for infection imaging. J. Nucl. Med.. 2003;47:238-245.
[Google Scholar]

[10] Lupetti A., Welling M.M., Pauwels E.K., Nibbering P.H., . Radiolabelled antimicrobial peptides for infection detection. Lancet Infect. Dis.. 2003;3:223-229.
[Google Scholar]

[11] Martin-Comin J., Soroa V., Rabiller G., Galli R., Cuesta L., Roca M., . Diagnosis of bone infection with 99mTc-ceftizoxime. Rev. Esp. Med. Nucl.. 2004;23:357.
[Google Scholar]

[12] Meléndez-Alafort L., Rodrìguez-Cortés J., Ferro-Flores G., Murphy C.A., Herrera-Rodrìguez R., Martìnez-Duncker C., . Biokinetics of ^99mTc-UBI in humans. Nucl. Med. Biol.. 2004;31:373-379.
[Google Scholar]

[13] Naqvi S.A.R., Ishfaq M.M., Khan Z.A., Nagra S.A., Bukhari I.H., Hussain A.I., Mahmood N., Shahzad S.A., Haque A., Bokhari T.H., . ^99mTc labeled levofloxacin as an infection imaging agent: a novel method for labeling levofloxacin using cysteine·HCl as co-ligand and in vivo study. Turk. J. Chem.. 2012;36:267-277.
[Google Scholar]

[14] Nibbering P.H., Welling M., van den Broek P.J., Pauwels E.K.J., . Radiolabeled antimicrobial peptides for imaging of infection: a review. Nucl. Med. Commun.. 1998;19:1117-1121.
[Google Scholar]

[15] Sarda L., Saleh-Mghir A., Peker C., Meulemans A., Crémieux A.C., Le Guludec D., . Evaluation of (99m)Tc-ciprofloxacin scintigraphy in a rabbit model of Streptococcus pneumoniae prosthetic joint infection. J. Nucl. Med.. 2002;43:239-245.
[Google Scholar]

[16] Sarda L., Crémieux A.C., Lebellec Y., Meulemans A., Lebtahi R., Hayem G., Génin R., Delahaye N., Huten D., Le Guludec D., . Inability of 99mTc-ciprofloxacin scintigraphy to discriminate between septic and sterile osteoarticular diseases. J. Nucl. Med.. 2003;44:920-926.
[Google Scholar]

[17] Siaens R.H., Rennen H.J., Boerman O.C., Dierckx R., Slegers G., . Synthesis and comparison of Tc-99m-enrofloxacin and Tc-99m-ciprofloxacin. J. Nucl. Med.. 2004;45:2088-2094.
[Google Scholar]

[18] Singh N., Bhatnagar A., . Clinical evaluation of efficacy of ^99mTc ethambutol in tubercular lesion imaging. Tuberc. Res. Treat. Hind. Pub. Corp. 2010:1-9.
[Google Scholar]

[19] Singh A.K., Verma J., Bhatnagar A., Ali A., . Tc-99m labeled sparfloxacin: a specific infection imaging agent. J. Nucl. Med.. 2003;2:103-109.
[Google Scholar]

[20] Vinjamuri S.H., Hall A.V., Solanki K.K., Bomanji J., Siraj Q., Shaughnessy E., Das S.S., Britton K.E., . Comparison of ^99mTc Infection imaging with radiolabeled white-cell imaging in the evaluation of bacterial infection. Lancet. 1996;347:233-235.
[Google Scholar]

[21] Welling M.M., Nibbering P.H., Paulusma-Annema A., Hiemstra P.S., Pauwels E.K., Calame W., . Imaging of bacterial infections with ^99mTc-labeled human neutrophil peptide-1. J. Nucl. Med.. 1999;40:2073-2080.
[Google Scholar]

[22] Welling M.M., Paulusma-Annema A., Balter H.S., Pauwels E.K., Nibbering P.H., . Technetium-99m labeled antimicrobial peptides discriminate between bacterial infections and sterile inflammations. Eur. J. Nucl. Med.. 2000;27:292-301.
[Google Scholar]

[23] Welling M.M., Lupetti A., Balter H.S., Lanzzeri S., Souto B., Rey A.M., Savio E.O., Paulusma-Annema A., Pauwels E.K., Nibbering P.H., . ^99mTc-labeled antimicrobial peptides for detection of bacterial and Candida albicans infections. J. Nucl. Med.. 2001;42:788-794.
[Google Scholar]

[24] Zijlstra S., Gunawan J., Freytag C., Burchert W., . Synthesis and evaluation of fluorine-18 labeled compounds for imaging of bacterial infections with PET. Appl. Radiat. Isot.. 2006;64:802-807.
[Google Scholar]