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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, December 2000, p. 3428-3431, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Bactericidal Activities of Antibiotics against
Intracellular Francisella tularensis
M.
Maurin,
N. F.
Mersali, and
D.
Raoult*
Unité des Rickettsies, CNRS UPRES A
6020, Faculté de Médecine, Université de la
Méditerranée, 13385 Marseille Cedex 05, France
Received 23 December 1999/Returned for modification 10 July
2000/Accepted 24 August 2000
 |
ABSTRACT |
MICs of many antibiotics for Francisella tularensis are
low in axenic medium, whereas only aminoglycosides, tetracyclines, and
fluoroquinolones are useful in treating tularemic patients. In an in
vitro cell system, only these antibiotics, rifampin, and telithromycin
were bactericidal against intracellular F. tularensis. These results correlate better with clinical data than MIC data do.
| |
TEXT |
Francisella
tularensis bv. tularensis and F. tularensis
bv. palearctica are responsible for tularemia
(17, 25). The geographical distribution of the former biovar
has long been considered restricted to North America, but this species
has recently been isolated from fleas and mites parasitizing small
mammals in Slovakia (15). This biovar is considered more
virulent in humans and animals than F. tularensis bv.
palearctica, which is found essentially in Europe and Asia
and to a lesser extent in North America. Antibiotic therapy of
tularemia has been empirically determined. Only streptomycin treatment
allows a 100% cure rate (7, 12). Because this antibiotic is
potentially toxic and may not be widely available nowadays, alternatives have been proposed. Gentamicin has been used successfully (5, 20) but has a similar toxicity potential. Tetracyclines are considered a useful alternative, although relapses are observed in
about 10% of cases (9, 24, 28). More recently,
fluoroquinolones have been useful in a limited number of patients
(26, 29, 31). Other antibiotics, including beta-lactams,
macrolides, and chloramphenicol, are considered less effective or
ineffective (4, 7, 9, 24). Only a few in vitro studies have
determined the antibiotic susceptibilities of F. tularensis.
Baker et al. (2) determined MICs for 15 F. tularensis strains, and they showed that the
expanded-spectrum cephalosporins (cefotaxime, ceftriaxone, and
ceftazidime), aminoglycosides, tetracycline, chloramphenicol,
erythromycin, and rifampin were all bacteriostatic. Similar results
were reported by Markowitz et al. (19). Thus, in vitro
susceptibility data do not correlate well with the clinical experience
in treating human tularemia. Because F. tularensis is a
facultative intracellular bacterium (10, 11, 14), we hypothesized that determination of the activity of antibiotics against
the intracellular form of the bacterium would yield more accurate
predictions of the clinical efficacy of antibiotics.
F. tularensis strain.
We used an F. tularensis bv. palearctica strain recently isolated in
our laboratory from a patient suffering from typical ulceroglandular
tularemia after receiving a tick bite in Mulhouse, northern France
(13).
MIC and MBC determination.
MICs were determined using a
modified Mueller-Hinton broth and a microplaque assay, as previously
described by Baker et al. (2). An F. tularensis
inoculum (~105 CFU/ml) was prepared from a chocolate
agar-grown culture (BioMérieux, Lyon, France) and dispensed into
the wells of a 96-well microtiter plate (Poly Labo, Paris,
France). Antibiotics were tested at twofold serial concentrations
(0.125 to 256 µg/ml) in triplicate. F. tularensis displayed exponential growth in modified minimum essential medium (MEM), with a 2.2-log increase in CFU counts after
24 h of incubation (37°C, 5% CO2). MICs were
determined after a 24-h incubation of antibiotic-containing cultures,
compared to drug-free controls. Minimal bactericidal concentrations
(MBCs) were determined at the same time, by plating onto chocolate agar
10-fold serial dilutions of bacterial suspensions from wells with no
visible growth; the minimal antibiotic concentration allowing a 3-log
or greater reduction of the primary bacterial inoculum titer was
considered the MBC.
Among beta-lactams tested, only ceftriaxone (an expanded-spectrum
cephalosporin) displayed a bacteriostatic activity (Table 1); none displayed a bactericidal
activity. Aminoglycosides (i.e., streptomycin, gentamicin, and
amikacin), thiamphenicol, macrolides (i.e., erythromycin,
clarithromycin, and telithromycin), rifampin, fluoroquinolones (i.e.,
ofloxacin, pefloxacin, and ciprofloxacin), and doxycycline displayed
both a bacteriostatic and a bactericidal activity against our F. tularensis strain, although only the MBCs of rifampin,
telithromycin, and fluoroquinolones were in the range of concentrations
achievable in human sera. Cotrimoxazole was poorly effective, but the
addition of vitamins in the Mueller-Hinton broth may have impaired the
activity of both sulfamethoxazole and trimethoprim as previously
mentioned by Baker et al. (2). These results are concordant
with MICs previously reported by Baker et al. for 15 F. tularensis strains isolated in the United States (2).
Intracellular antibiotic susceptibility testing.
F.
tularensis was grown in P388D1 murine macrophage-like cells (ATCC
CCL46). Confluent cell monolayers grown in shell vials (Bibby Sterilin,
Stome, Staffordshire, England) were seeded with 1 ml of a
107-CFU/ml F. tularensis inoculum, in MEM
supplemented with 10% fetal calf serum (Poly Labo) and 2 mM glutamine
(Poly Labo), and immediately centrifuged (1 h, 3,500 × g, room temperature). In order to remove nonphagocytized bacteria,
cell supernatants were replaced by MEM containing 10 µg of gentamicin
per ml, and cultures were incubated at 37°C for 4 h. We
previously determined that such a protocol allowed a 4-log reduction of
an F. tularensis inoculum. Because penetration of eukaryotic
cells by gentamicin is slow, detectable only after 24 to 48 h of
antibiotic exposure (33, 34), this protocol would allow
eradication of nonphagocytized bacteria without significant killing of
intracellular F. tularensis. Gentamicin-containing supernatants were then discarded and replaced by MEM supplemented with
4% fetal calf serum and 2 mM glutamine, which does not support extracellular growth of F. tularensis. Antibiotics were
added to culture media at a single concentration in the range of levels achievable in the serum of humans (Fig.
1). As for ceftriaxone and gentamicin,
approximately peak and trough concentrations in serum were used (Fig.
1). Tests were made in triplicate and repeated for confirmation of
results. All cultures were incubated at 37°C in a 5%
CO2-enriched atmosphere. Titration of the primary bacterial inoculum and residual viable bacterial counts after the various incubation times was achieved by plating 10-fold serial dilutions of
cell lysates onto chocolate agar plates, after replacing the shell vial
supernatant by 1 ml of drug-free MEM, harvesting cell monolayers by
scraping, and inducing cell lysis by thermic shocks (
180 and 37°C
three times). Plates were incubated (37°C, 5% CO2) until
colonies were visible, and CFU counts were determined. A bactericidal
activity corresponded to a significant decrease in CFU counts after
antibiotic exposure compared to the primary inoculum dose, as
determined by using the Student t test and a 95% confidence
limit. The lack of cell toxicity of both the experimental procedure and
the antibiotics used was verified by (i) examination of cell monolayers
under an inverted microscope before each inoculum titration and (ii)
repeating the experimental procedure and, using trypan blue dye
exclusion test, determining cell viability, which was considered
acceptable if fewer than 2% of cells were stained (Sigma, Paris,
France).
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FIG. 1.
Activities of antibiotics against intracellular F. tularensis. (A) Penicillin G (10 µg/ml), amoxicillin (10 µg/ml), ceftriaxone (10 and 100 µg/ml), streptomycin (10 µg/ml),
gentamicin (3 and 10 µg/ml), and amikacin (10 µg/ml). (B)
Doxycycline (4 µg/ml), thiamphenicol (4 µg/ml), rifampin (4 µg/ml), trimethoprim-sulfamethoxazole (10 and 50 µg/ml,
respectively), erythromycin (4 µg/ml), clarithromycin (4 µg/ml),
telithromycin (4 µg/ml), ofloxacin (1 µg/ml), and ciprofloxacin (1 µg/ml). I/Io, ratio of the viable bacterial titers (CFU per
milliliter), after 24, 48, or 72 h of incubation of cultures in
the presence of the various antibiotics tested to the primary F. tularensis inoculation dose. Data correspond to a single
experiment performed in triplicate. All data points with at least a
1-log decrease were statistically significantly different from controls
(P < 0.001).
|
|
F. tularensis multiplied within P388D1 macrophage-like
cells, with a 0.65-log increase in CFU after a 24-h incubation of
cultures, whereas stagnation in CFU counts was observed after 48 h
of incubation (Fig. 1), and incubation prolonged to 72 h resulted
in the complete destruction of cell monolayers, preventing the
determination of CFU counts in controls at that time. No cell toxicity
was observed with antibiotics at the concentrations tested. Penicillin
G, amoxicillin, ceftriaxone, thiamphenicol, and erythromycin failed to
display any significant activity against intracellular F. tularensis compared to drug-free controls after 24- and 48-h
incubations (Fig. 1), whereas incubation prolonged to 72 h
resulted in the destruction of cell monolayers, which can be considered
evidence of lack of intracellular bacteriostatic activity as well. In
contrast, infected cells remained viable for the 3-day period of the
experiments in cultures containing antibiotics with significant
intracellular bactericidal activity, including the aminoglycosides
streptomycin, gentamicin, and amikacin, but also telithromycin,
doxycycline, rifampin, and the fluoroquinolones ofloxacin and
ciprofloxacin (Fig. 1).
Location of F. tularensis within P388D1 cells.
The
location of F. tularensis within P388D1 cells was assessed
both by a transmission electron microscopy technique and by confocal
microscopy analysis. P388D1 cells were infected with F. tularensis using the previously described procedure,
including the use of gentamicin to remove nonphagocytized bacteria.
Infected cell cultures were then incubated at 37°C in drug-free
supplemented MEM for 48 h. In the electron microscopy
assessment, infected P388D1 cells were harvested by trypsinization and
pelleted by centrifugation. Cell pellets were fixed (1 h at room
temperature) in cacodylate buffer (0.1 M, pH 7.2) containing
2.5% glutaraldehyde and then incubated overnight at 4°C
in fresh cacodylate buffer. They were incubated (1 h at room
temperature) in 1% osmium tetroxide, dehydrated through
increasing concentrations (25 to 100%) of ethanol, and then
embedded in Epon 812. Thin sections were cut out and poststained with a
saturated solution of methanol-uranyl acetate and lead citrate in water
before examination on a JEOL JEM 1200 EX electron microscope. In
the confocal microscopy assessment, F. tularensis-infected P388D1 cells were grown on 10-mm-diameter coverslips in shell vials. After a 48-h incubation of cultures, F. tularensis was stained by indirect
immunofluorescence, using a locally prepared rabbit
anti-F. tularensis serum (1:200) and a goat
anti-rabbit immunoglobulin-fluorescein conjugate (1:200) (BioMérieux, Marcy L'Etoile, France). Cells were stained by
using Evan's blue dye (BioMérieux). Fluorescence was analyzed
with a laser scanning confocal fluorescence microscope (LEICA
DMIRBE) equipped with a 100× (numerical aperture, 1.4) oil
immersion lens. The intracellular location of F. tularensis,
in infected P388D1 cell cultures, was confirmed both by electron
microscopy and by confocal microscopy analysis. An electron micrograph
of F. tularensis-infected P388D1 cells showed that
after 48 h of incubation bacteria were localized within vacuoles.
These vacuoles were of variable size and contained one to several
bacteria. Likewise, confocal microscopy revealed the presence of
several fluorescent intracellular bacteria within each infected cell examined.
Results obtained in our cell model correlate well with current clinical
experience in treating human tularemia and explain for the first time
some previously mentioned discrepancies. First, the observation that
aminoglycosides display high in vitro activity against extracellular
but also intracellular F. tularensis is compatible with
their usefulness in treating tularemic patients (7, 20).
These results confirm early observations by Nutter and Myrvik
(23) that streptomycin but not penicillin G could inhibit
growth of F. tularensis within rabbit alveolar macrophages in vitro. Also, our results are compatible with current knowledge of
the pharmacokinetic properties of this class of antibiotics. Thus,
activity of aminoglycosides against intracellular F. tularensis increased progressively with prolonged incubation time,
reaching a maximum after 72 h of incubation of cultures, which
correlates well with the mechanism of pinocytosis by which
aminoglycosides progressively concentrate within eukaryotic cells,
reaching significant intracellular levels only after 48 to 72 h of
antibiotic-cell contact (21, 33, 34). Although
expanded-spectrum cephalosporins display high in vitro activity against
F. tularensis, Cross et al. (4, 5) reported a
100% failure rate in eight tularemic patients treated with
ceftriaxone. Ceftriaxone was bacteriostatic against F. tularensis in axenic medium. However, although ceftriaxone has been shown to penetrate within phagocytic cells
(18), the lack of bactericidal activity against both
extracellular and intracellular F. tularensis may well
explain why this compound cannot cure F. tularensis-infected patients (4, 7). The same reasoning may apply to thiamphenicol and erythromycin, compounds for which relapse rates in tularemic patients are high (4, 7) and which lack any bactericidal activity against F. tularensis
despite their intracellular accumulation (21). Rifampin
penetrates well within eukaryotic cells and displays a significant
activity against intracellular F. tularensis. However, this
compound is not considered a safe alternative to treat tularemia
because of frequent relapses upon antibiotic withdrawal (7).
In vitro selection of rifampin-resistant mutants has been previously
reported for F. tularensis (3) as well as
for many other bacteria (1, 8, 16, 22, 32) and may
well explain the poor clinical efficacy of this compound when used
alone. Doxycycline can inhibit F. tularensis growth in
broth and displays a bactericidal activity in P388D1 cells, which
correlates well with the usefulness of tetracycline compounds in
patients with tularemia. However, the frequent occurrence of clinical
relapses (7, 9) when a tetracycline is administered may
indicate that in vivo activity is merely bacteriostatic. As for
the fluoroquinolones, a high activity against F. tularensis was shown both in axenic medium and in cells, which
fits well with current clinical experience in using these drugs to
treat tularemic patients (29, 31). Newer macrolide compounds
potentially represent a safe alternative in populations for which
tetracyclines and fluoroquinolones are contraindicated, including
pregnant women and children. Interestingly, the ketolide telithromycin
displays a bactericidal activity against F. tularensis in
axenic medium and in our cell system. Telithromycin has been shown to
reach high intracellular concentrations in polymorphonuclear
neutrophils (35) and is highly active in vitro
against other intracellular pathogens, including Chlamydia
(27) and Legionella (6, 30). Its
activity against intracellular F. tularensis warrants
clinical trials to establish its clinical usefulness in treating
patients with tularemia.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Unité des
Rickettsies, CNRS UPRES A 6020, Faculté de Médecine,
Université de la Méditerranée, 27 Boulevard Jean
Moulin, 13385 Marseille Cedex 05, France. Phone: (33) 4 91 38 55 17. Fax: (33) 4 91 83 03 90. E-mail:
Didier.Raoult{at}medecine.univ-mrs.fr.
| |
REFERENCES |
| 1.
|
Aubry-Damon, H.,
C.-J. Soussy, and P. Courvalin.
1998.
Characterization of mutations in the rpoB gene that confer rifampin resistance in Staphylococcus aureus.
Antimicrob. Agents Chemother.
42:2590-2594[Abstract/Free Full Text].
|
| 2.
|
Baker, C. N.,
D. G. Hollis, and C. Thornsberry.
1985.
Antimicrobial susceptibility testing of Francisella tularensis with a modified Mueller-Hinton broth.
J. Clin. Microbiol.
22:212-215[Abstract/Free Full Text].
|
| 3.
|
Bhatnagar, N.,
E. Getachew,
S. Straley,
J. Williams,
M. Meltzer, and A. Fortier.
1994.
Reduced virulence of rifampicin-resistant mutants of Francisella tularensis.
J. Infect. Dis.
170:841-847[Medline].
|
| 4.
|
Cross, J. T., and R. F. Jacobs.
1993.
Tularemia: treatment failures with outpatient use of ceftriaxone.
Clin. Infect. Dis.
17:976-980[Medline].
|
| 5.
|
Cross, J. T. J.,
G. E. Schutze, and R. F. Jacobs.
1995.
Treatment of tularemia with gentamicin in pediatric patients.
Pediatr. Infect. Dis. J.
14:151-152[Medline].
|
| 6.
|
Edelstein, P. H., and M. A. C. Edelstein.
1999.
In vitro activity of the ketolide HMR 3647 (RU 6647) for Legionella spp., its pharmacokinetics in guinea pigs, and use of the drug to treat guinea pigs with Legionella pneumophila pneumonia.
Antimicrob. Agents Chemother.
43:90-95[Abstract/Free Full Text].
|
| 7.
|
Enderlin, G.,
L. Morales,
R. F. Jacobs, and J. T. Cross.
1994.
Streptomycin and alternative agents for the treatment of tularemia: review of the literature.
Clin. Infect. Dis.
19:42-47[Medline].
|
| 8.
|
Enright, M.,
P. Zawadski,
P. Pickerill, and C. G. Dowson.
1998.
Molecular evolution of rifampicin resistance in Streptococcus pneumoniae.
Microb. Drug Resist.
4:65-70[Medline].
|
| 9.
|
Evans, M. E.,
D. W. Gregory,
W. Schaffner, and Z. A. McGee.
1985.
Tularemia: a 30-year experience with 88 cases.
Medicine
64:251-269[Medline].
|
| 10.
|
Fortier, A. H.,
D. A. Leiby,
R. B. Narayanan,
E. Asafoadjei,
R. M. Crawford,
C. A. Nacy, and M. S. Meltzer.
1995.
Growth of Francisella tularensis LVS in macrophages: the acidic intracellular compartment provides essential iron required for growth.
Infect. Immun.
63:1478-1483[Abstract].
|
| 11.
|
Fortier, A. H.,
T. Polsinelli,
S. J. Green, and C. A. Nacy.
1992.
Activation of macrophages for destruction of Francisella tularensis: identification of cytokines, effector cells, and effector molecules.
Infect. Immun.
60:817-825[Abstract/Free Full Text].
|
| 12.
|
Foshay, L., and A. B. Pasternack.
1946.
Streptomycin treatment of tularemia.
JAMA
130:393-398.
|
| 13.
|
Fournier, P.-E.,
L. Bernabeu,
B. Schubert,
M. Mutillod,
V. Roux, and D. Raoult.
1998.
Isolation of Francisella tularensis by centrifugation of shell vial cell culture from an inoculation eschar.
J. Clin. Microbiol.
36:2782-2783[Abstract/Free Full Text].
|
| 14.
|
Fujita, H.,
Y. Watanabe,
T. Sato,
Y. Ohara, and M. Homma.
1993.
The entry and intracellular multiplication of Francisella tularensis in cultured cells: its correlation with virulence in experimental mice.
Microbiol. Immunol.
37:837-842[Medline].
|
| 15.
|
Gurycova, D.
1998.
First isolation of Francisella tularensis subsp. tularensis in Europe.
Eur. J. Epidemiol.
14:797-802[Medline].
|
| 16.
|
Heep, M.,
D. Beck,
E. Bayerdörffer, and N. Lehn.
1999.
Rifampin and rifabutin resistance mechanism in Helicobacter pylori.
Antimicrob. Agents Chemother.
43:1497-1499[Abstract/Free Full Text].
|
| 17.
|
Jacobs, R. F.
1997.
Tularemia.
Adv. Pediatr. Infect. Dis.
12:55-68.
|
| 18.
|
Kuhn, H.,
P. Angehrn, and L. Havas.
1986.
Autoradiographic evidence for penetration of 3H-ceftriaxone (Rocephin) into cells of spleen, liver and kidney of mice.
Chemotherapy
32:102-112[Medline].
|
| 19.
|
Markowitz, I. E.,
N. A. Hynes, and P. de la Cruz.
1985.
Tick-borne tularemia. An outbreak of lymphadenopathy in children.
JAMA
254:2922-2925[Abstract].
|
| 20.
|
Mason, W. L.,
H. T. Eigelsbach,
S. F. Little, and J. H. Bates.
1980.
Treatment of tularemia, including pulmonary tularemia, with gentamicin.
Am. Rev. Respir. Dis.
121:39-45[Medline].
|
| 21.
|
Maurin, M., and D. Raoult.
1993.
Antibiotic penetration within eukaryotic cells, p. 21-37.
In
D. Raoult (ed.), Antimicrobial agents and intracellular pathogens. CRC Press, Boca Raton, Fla.
|
| 22.
|
Morse, R.,
K. O'Hanlon,
M. Virji, and M. D. Collins.
1999.
Isolation of rifampin-resistant mutants of Listeria monocytogenes and their characterization by rpoB gene sequencing, temperature sensitivity for growth, and interaction with an epithelial cell line.
J. Clin. Microbiol.
37:2913-2919[Abstract/Free Full Text].
|
| 23.
|
Nutter, J. E., and Q. N. Myrvik.
1966.
In vitro interactions between rabbit alveolar macrophages and Pasteurella tularensis.
J. Bacteriol.
92:645-651[Abstract/Free Full Text].
|
| 24.
|
Parker, R.,
L. Lister,
R. Bauer, et al.
1950.
Use of chloramphenicol (chloromycetin) in experimental and human tularemia.
JAMA
143:7-11.
|
| 25.
|
Penn, R. L.
1995.
Francisella tularensis (tularemia), p. 2060-2068.
In
G. L. Mandell, J. E. Bennett, and R. Dolin (ed.), Principles and practice of infectious diseases, 4th ed. Elsevier, New York, N.Y.
|
| 26.
|
Risi, G. F., and D. J. Pombo.
1995.
Relapse of tularemia after aminoglycoside therapy: case report and discussion of therapeutic options.
Clin. Infect. Dis.
20:174-175[Medline].
|
| 27.
|
Roblin, P. M., and M. R. Hammerschlag.
1998.
In vitro activity of a new ketolide antibiotic, HMR 3647, against Chlamydia pneumoniae.
Antimicrob. Agents Chemother.
42:1515-1516[Abstract/Free Full Text].
|
| 28.
|
Sanders, C. V., and R. Hahn.
1968.
Analysis of 106 cases of tularemia.
J. La. State Med. Soc.
120:391-393[Medline].
|
| 29.
|
Scheel, O.,
R. Reiersen, and T. Hoel.
1991.
Treatment of tularemia with ciprofloxacin.
Eur. J. Clin. Microbiol. Infect. Dis.
11:447-448.
|
| 30.
|
Schülin, T.,
C. B. Wennersten,
M. J. Ferraro,
R. C. Moellering, Jr., and G. M. Eliopoulos.
1998.
Susceptibilities of Legionella spp. to newer antimicrobials in vitro.
Antimicrob. Agents Chemother.
42:1520-1523[Abstract/Free Full Text].
|
| 31.
|
Syrjälä, H.,
R. Schildt, and S. Räisäinen.
1991.
In vitro susceptibility of Francisella tularensis to fluoroquinolones and treatment of tularemia with norfloxacin and ciprofloxacin.
Eur. J. Clin. Microbiol. Infect. Dis.
10:68-70[CrossRef][Medline].
|
| 32.
|
Telenti, A.,
P. Imboden,
F. Marchesi,
D. Lowrie,
S. Cole,
M. J. Colston,
L. Matter,
K. Schopfer, and T. Bodmer.
1993.
Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis.
Lancet
341:647-650[CrossRef][Medline].
|
| 33.
|
Tulkens, P., and A. Trouet.
1974.
Uptake and intracellular localization of kanamycin and gentamycin in the lysosomes of cultured fibroblasts.
Arch. Int. Physiol. Biochim.
82:1018-1019[Medline].
|
| 34.
|
Tulkens, P., and A. Trouet.
1978.
The uptake and intracellular accumulation of aminoglycoside antibiotics in lysosomes of cultured rat fibroblasts.
Biochem. Pharmacol.
27:415-424[CrossRef][Medline].
|
| 35.
|
Vazifeh, D.,
A. Preira,
A. Bryskier, and M. T. Labro.
1998.
Interactions between HMR 3647, a new ketolide, and human polymorphonuclear neutrophils.
Antimicrob. Agents Chemother.
42:1944-1951[Abstract/Free Full Text].
|
Antimicrobial Agents and Chemotherapy, December 2000, p. 3428-3431, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Maurin, M., Raoult, D.
(2001). Use of Aminoglycosides in Treatment of Infections Due to Intracellular Bacteria. Antimicrob. Agents Chemother.
45: 2977-2986
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