Download MINERVA MEDICA COPYRIGHT ® Labeling of antibiotics for

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. Siaens RH, Rennen HJ, Boerman OC, Dierckx R, Slegers G.
Synthesis and comparison of 99mTc-Enrofloxacino and 99mTcCiprofloxacin. J Nucl Med 2004;45:2088-95.
12. Gomes Barreto V, Iglesias F, Roca M, Tubau F, Martin-Comin J.
THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
151
BENITEZ
13.
[Labelling of ceftizoxime with 99mTc]. Rev Esp Med Nucl 2000;19:47983.
Venjamuri S, Hall AV, Solanki KK, Bomanji J, Siraj Q, O’Shanghnessy
E et al. Comparison of 99mTc infecton imaging with radiolabelled
white-cell imaging in the evaluation of bacterial infection. Lancet
1996;347:233-5.
Hooper DC, Wolfson JS, Ng EY, Swartz MN. Mechanisms of action
of and resistance to ciprofloxacin. Am J Med 1987;82:12-20.
O’Donnell JA, Gelone SP. Fluoroquinolones. Infect Dis Clin North
Am 2000;14:489-513, xi.
King DE, Malone R, Lilley SH. New classification and update on
the quinolone antibiotics. Am Fam Physician 2000;61:2741-8.
Hall AV, Solanki KK, Vinjamuri S, Britton KE, Das SS. Evaluation
of the efficacy of 99mTc-Infecton, a novel agent for detecting sites
of infection. J Clin Path 1998;51:215-9.
De Winter F, Van de Wiele C, Dumont F, Van Durme J, Solanki K,
Britton K et al. Biodistribution and dosimetry of 99mTc-ciprofloxacin,
a promising agent for the diagnosis of bacterial infection. Eur J Nucl
Med 2001;28:570-4.
Easmon CSF, Crane JP, Blowers A. Effect of ciprofloxacin on intracellular organisms: in-vitro and in-vivo studies. J Antimicrob
Chemother 1986;18 Suppl D:43-8.
Britton KE, Soroa V, Amaral H, Malamitsi J, Kartamihardja H,
Sundrum F et al. 99mTc-”infecton”, preliminary evaluation in over 500
patients through an IAEA co-ordinated research programme. Eur
J Nucl Med 1998;25:OS 152.
Larikka MJ, Ahonen AK, Niemela O, Junila JA, Hamalainen MM,
Britton K et al. Comparison of 99mTc-ciprofloxacin, 99mTc-whiteblood cell and three-phase bone imaging in the diagnosis of hip
prosthesis infections: improved diagnostic accuracy with extended imaging time. Nucl Med Commun 2002;23:655-61.
Dumarey N, Blocklet D, Appelboom T, Tant L, Schoutens A.
23.
24.
Infecton is not specific for bacterial osteo-articular infective pathology. Eur J Nucl Med Mol Imaging 2002;29:530-5.
Sarda L, Cremieux AC, Lebellec Y, Meulemans A, Lebatahi R,
Hayem G et al. Inability of 99mTc-Ciprofloxacin scintigraphy to discriminate between septic and sterile osteoarticular diseases. J Nucl
Med 2003;44:920-6.
Britton KE, Wareham DW, Das SS, Solanki KK, Amaral H, Bhatnagar
A et al. Imaging bacterial infection with (99m)Tc-ciprofloxacin
(Infecton). J Clin Pathol 2002;55:817-23.
Sharma S, Tripathi M, Kabra SK, Gupta R, Malhotra A. Prospective
evaluation of 99mTc-Ciprofloxacin in pyrexia of unknown origin. Eur
J Nucl Med, 2005;32 Suppl 1:S226:P538.
Artiko V, Davidovic B, Nikolic N, Petrovic M, Vlajkovic M, Pesko
P et al. Detection of gastrointestinal and abdominal infections by
99m
Tc-ciprofloxacin. Hepatogastroenterology 2005;52:491-5.
Hooper DC, Wolfson JS, Ng EY, Swartz MN. Mechanisms of action
of and resistance to ciprofloxacin. Am J Med 1987;82:12-20.
Decristoforo C, Mather SJ. 99mTechnetium-labelled peptide-HYNIC
conjugales: effects of lipophilicity and stability on biodistribution.
Nucl Med Biol 1999;26:389-96.
Pirmettis I, Limouris GS, Papadopoulos M, Chiotellis E. Potential
infection imaging agents: preparation and biodistribution of 99mTcnorfloxacin and 99mTc-ciprofloxacin. Eur J Nucl Med 2000;27;PS-224.
Fu KP, Neu HC. Antibacterial activity of ceftizoxime, a beta-lactamase-stable cephalosporin. Antimicrob Agents Chemother
1980;17:583-90.
Gomes Barreto V, Iglesias F, Roca M, Tubau F, Martín-Comín J.
Biodistribution of Tc-99m-ceftizoxime in animal model infection
and inflammation. Eur J Nucl Med 2000;27:970.
Soroa VE, Velazquez Espeche MD, Rabiller G, Roca M, Martín
Comin J. Infection images: behavior of Ceftizoxime a 99mTc radiollabeled antibiotic. Eur J Nucl Med 2005;32 Suppl 1:S226-P539.
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