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Antimicrobial Agents and Chemotherapy, May 2000, p. 1391-1393, Vol. 44, No. 5
Unité des Rickettsies, CNRS UPRES-A
6020, Faculté de Médecine, Université de la
Méditerranée, 13385 Marseille Cedex
05,1 and Anti-Infective Research
Department, Hoechst-Marion-Roussel, 93235 Romainville,2 France
Received 7 September 1999/Returned for modification 22 December
1999/Accepted 26 January 2000
In vitro activities of telithromycin compared to those of
erythromycin against Rickettsia spp.,
Bartonella spp., Coxiella burnetii, and
Ehrlichia chaffeensis were determined. Telithromycin was
more active than erythromycin against Rickettsia,
Bartonella, and Coxiella burnetii, with MICs of
0.5 µg/ml, 0.003 to 0.015 µg/ml, and 1 µg/ml, respectively, but
was inactive against Ehrlichia chaffeensis.
Telithromycin belongs to a new class
of erythromycin derivatives, the ketolides, that have activity against
a wide variety of bacterial species (1, 20), including
intracellular bacteria such as Chlamydia pneumoniae and
Legionella spp. (15, 18). In this study we have
evaluated the antimicrobial activities of telithromycin against various
rickettsial pathogens, including Rickettsia spp.,
Ehrlichia spp., and Bartonella spp., which belong to the The antibiotics used in this study were doxycycline, erythromycin, and
telithromycin (Hoescht Marion Roussel, Romainville, France). The
strains tested are specified in Table 1
and Fig. 1. The bacteriostatic activities
of telithromycin and erythromycin against Rickettsia spp.
were evaluated by a dye uptake assay and a plaque assay in Vero cells,
as previously described (13). For Bartonella spp.
a modified version of the antibiotic agar dilution method of the
National Committee for Clinical Laboratory Standards was used for
determination of MICs (9, 19). The bactericidal
activities of antibiotics against Bartonella spp. were
determined in a broth assay, using liquid Schaedler medium (Bio
Merieux, Lyon, France) supplemented with 10% horse blood. One
milliliter of this medium with or without antibiotics was placed in a
glass tube filled with 106 CFU of bacteria per ml for
24 h. Tenfold serial dilutions of each tube culture were plated
onto blood-agar and reincubated for 5 to 6 days before enumeration of
colonies. The minimal bactericidal concentration was defined as the
minimal concentration of the antibiotic inducing a 99.9% decrease in
bacterial inocula.
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
In Vitro Activities of Telithromycin (HMR 3647)
against Rickettsia rickettsii, Rickettsia
conorii, Rickettsia africae, Rickettsia
typhi, Rickettsia prowazekii, Coxiella
burnetii, Bartonella henselae, Bartonella
quintana, Bartonella bacilliformis, and
Ehrlichia chaffeensis
ABSTRACT
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group of Proteobacteria, and Coxiella
burnetii, which belongs to the 
group of
Proteobacteria (17). Tetracyclines are the
mainstay antibiotics to treat patients with rickettsiosis, acute Q
fever, and ehrlichiosis, with fluoroquinolones being alternatives for
the two former diseases. However, both agents are contraindicated in
children and pregnant women. Erythromycin is the first-line antibiotic
therapy for bacillary angiomatosis due to Bartonella quintana or Bartonella henselae, with tetracyclines as
a possible alternative. Ketolides may represent a safe alternative for
treatment of all of these diseases, especially during childhood and pregnancy.
TABLE 1.
MICs of telithromycin and erythromycin against
Rickettsia and Bartonella species and
against C. burnetii
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FIG. 1.
Susceptibilities of E. chaffeensis to
doxycycline and telithromycin, as determined by a microplate
colorimetric assay (4). Only results obtained with 8 µg of
telithromycin per ml or 1 µg of doxycycline per ml are presented.
The bacteriostatic activity of telithromycin against C. burnetii was determined by the shell-vial assay with HEL cells (14), whereas the bactericidal activity was evaluated by a quantitative model previously described (8). Antibiotic susceptibility for Ehrlichia was determined by a microplate assay using DH82 cells, as previously described (4). Antibiotics were added to the culture medium, and the MIC was defined as the lowest antibiotic concentration capable of preventing growth during the 72 h of antibiotic exposure. Bactericidal effect was defined as lack of bacterial regrowth within the 6 days following antibiotic removal. Telithromycin was tested at twofold serial concentrations ranging from 0.25 to 8 µg/ml, and doxycycline was tested at concentrations ranging from 0.25 to 1 µg/ml.
The results of the testing of the in vitro activities of telithromycin
against different bacterial strains are summarized in Table 1. Growth
of all strains of Rickettsia spp., C. burnetii, and Bartonella spp. was inhibited by telithromycin at
concentrations of 
0.5 µg/ml. Telithromycin was more active than
erythromycin against all these bacteria, except for Rickettsia
typhi and Rickettsia prowazekii, which were inhibited
by similar concentrations of erythromycin or telithromycin.
Telithromycin did not display any bactericidal activity at
concentrations of 4 µg/ml against Rickettsia spp. or
Bartonella spp. The bactericidal activity of telithromycin was evaluated on the C. burnetii Nine Mile and Q212 strains.
The primary inoculum for the Nine Mile strain was 3 × 105 IU/ml, and the primary inoculum for the Q212 strain was
6 × 106 IU/ml. Residual concentrations of viable
bacteria, after 24 h of incubation with telithromycin at 4 µg/ml, were 105 and 2 × 106 IU/ml for
the Nine Mile and Q212 strains, respectively. No significant differences in bacterial titers, as determined by Student's
t test at the 95% confidence limit, were noted between
untreated controls and cultures receiving 4 µg per of telithromycin
per ml. Telithromycin at concentrations of 0.25 to 8 µg/ml was
ineffective against Ehrlichia chaffeensis, as the infection
increased in telithromycin-containing cultures in the same manner as in
untreated controls (Fig. 1).
We found that telithromycin was more active than erythromycin against Rickettsia sp., C. burnetii, and Bartonella sp. strains, whereas it was not effective against E. chaffeensis. These results are in accordance with previous reports on the in vitro activities of various macrolide compounds against these pathogens (6, 7, 10, 16). As for rickettsiosis, tetracyclines remain the antibiotics of choice, with fluoroquinolones being an alternative (11). Nevertheless, adverse effects of these compounds either limit or contraindicate their use, especially during pregnancy and childhood. A wide variability in the susceptibilities of rickettsiae to different macrolide compounds has been described (6, 10, 16). We have previously shown that josamycin is the most effective macrolide compound in vitro against rickettsiae (16), and successful treatment with josamycin in children and pregnant women suffering from Mediterranean spotted fever (2, 12) has been reported; thus, telithromycin may represent a safe alternative in these situations.
Erythromycin is not currently considered a safe alternative in acute Q fever treatment owing to the fact that therapeutic failures with this antibiotic, probably due to heterogeneous susceptibility to erythromycin among different C. burnetii strains, have been reported (10). The lower MICs of telithromycin that have been found may correspond to a better in vivo activity.
Infections due to E. chaffeensis are treated with tetracyclines. In vitro, rifampin is also effective (4), but clinical trials using this drug are lacking. Like erythromycin, telithromycin was not effective against E. chaffeensis and should not be evaluated in human ehrlichiosis.
Erythromycin is the antibiotic therapy currently recommended for immunocompromised patients with bacillary angiomatosis (8), and azithromycin has been used successfully to treat patients with local suppuration or systemic manifestations of cat scratch disease (3, 5).
In conclusion, the new ketolide compound telithromycin is highly effective against Rickettsia and Bartonella species and C. burnetii, and clinical trials using this drug, at least for rickettsiosis, acute Q fever, and bacillary angiomatosis, are warranted.
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ACKNOWLEDGMENTS |
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This study was supported by a grant from Hoescht Marion Roussel.
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FOOTNOTES |
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* Corresponding author. Mailing address: Unité des Rickettsies, Faculté de Médecine, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France. Phone: 33 04 91 32 43 75. Fax: 33 04 91 38 77 72. E-mail: Didier.Raoult{at}medecine.univ-mrs.fr.
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REFERENCES |
|---|
|
Top
Abstract
Text
References
|
|---|
| 1. |
Barry, A. L.,
P. C. Fuchs, and S. D. Brown.
1998.
In vitro activities of the ketolide HMR 3647 against recent gram-positive clinical isolates and Haemophilus influenzae.
Antimicrob. Agents Chemother.
42:2138-2140 |
| 2. |
Bella, F.,
B. Font,
S. Uriz,
T. Munoz,
E. Espejo-Arenas,
J. Traveria,
J. A. Serrano, and F. Segura.
1990.
Randomized trial of doxycycline versus josamycin for Mediterranean spotted fever.
Antimicrob. Agents Chemother.
34:937-938 |
| 3. | Bogue, C. W., J. D. Wise, G. F. Gray, and K. M. Edwards. 1989. Antibiotic therapy for cat-scratch disease. JAMA 262:813-816[Abstract]. |
| 4. |
Brouqui, P., and D. Raoult.
1992.
In vitro antibiotic susceptibility of the newly recognized agent of ehrhlichiosis in humans, Ehrlichia chaffeensis.
Antimicrob. Agents Chemother.
36:2799-2803 |
| 5. | Carithers, H. A. 1985. Cat-scratch disease: an overview based on a study of 1200 patients. Am. J. Dis. Child. 139:1124-1133[Abstract]. |
| 6. | Ives, T. J., P. Manzewitsch, R. L. Regnery, J. D. Butts, and M. Kebede. 1997. In vitro susceptibilities of Bartonella henselae, B. quintana, B. elizabethae, Rickettsia rickettsia, R. conorii, R. akari, and R. prowazekii to macrolide antibiotics as determined by immunofluorescent-antibody analysis of infected vero cell monolayers. Antimicrob. Agents Chemother. 41:578-582[Abstract]. |
| 7. |
Keysary, A.,
A. Itzhaki,
E. Rubinstein,
C. Oron, and G. Keren.
1996.
The in-vitro anti-rickettsial activity of macrolides.
J. Antimicrob. Chemother.
38:727-731 |
| 8. | Maurin, M., A. M. Benoliel, P. Bongrand, and D. Raoult. 1992. Phagolysosomal alkalinization and the bactericidal effect of antibiotics: the Coxiella burnetii paradigm. J. Infect. Dis. 166:1097-1102[Medline]. |
| 9. | Maurin, M., S. Gasquet, C. Ducco, and D. Raoult. 1995. MICs of 28 antibiotic compounds for 14 Bartonella (formerly Rochalimaea) isolates. Antimicrob. Agents Chemother. 39:2387-2391[Abstract]. |
| 10. |
Maurin, M., and D. Raoult.
1993.
In vitro susceptibilities of spotted fever group rickettsiae and Coxiella burnetii to clarithromycin.
Antimicrob. Agents Chemother.
37:2633-2637 |
| 11. | Maurin, M., and D. Raoult. 1996. Optimum treatment of intracellular infection. Drugs 52:45-59[Medline]. |
| 12. |
Raoult, D., and M. Drancourt.
1991.
Antimicrobial therapy of rickettsial diseases.
Antimicrob. Agents Chemother.
35:2457-2462 |
| 13. | Raoult, D., P. Roussellier, G. Vestris, and J. Tamalet. 1987. In vitro antibiotic susceptibility of Rickettsia rickettsii and Rickettsia conorii: plaque assay and microplaque colorimetric assay. J. Infect. Dis. 155:1059-1062[Medline]. |
| 14. |
Raoult, D.,
H. Torres, and M. Drancourt.
1991.
Shell-vial assay: evaluation of a new technique for determining antibiotic susceptibility, tested in 13 isolates of Coxiella burnetii.
Antimicrob. Agents Chemother.
35:2070-2077 |
| 15. |
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 |
| 16. |
Rolain, J. M.,
M. Maurin,
G. Vestris, and D. Raoult.
1998.
In vitro susceptibilities of 27 rickettsiae to 13 antimicrobials.
Antimicrob. Agents Chemother.
42:1537-1541 |
| 17. |
Roux, V.,
E. Rydkina,
M. Eremeeva, and D. Raoult.
1997.
Citrate synthase gene comparison, a new tool for phylogenetic analysis, and its application for the rickettsiae.
Int. J. Syst. Bact.
47:252-261 |
| 18. |
Schulin, T.,
C. B. Wennersten,
M. J. Ferraro,
R. C. J. Moellering, and G. M. Eliopoulos.
1998.
Susceptibilities of Legionella spp. to newer antimicrobials in vitro.
Antimicrob. Agents Chemother.
42:1520-1523 |
| 19. |
Sobraquès, M.,
M. Maurin,
R. Birtles, and D. Raoult.
1999.
In vitro susceptibilities of four Bartonella bacilliformis strains to 30 antibiotic compounds.
Antimicrob. Agents Chemother.
43:2090-2092 |
| 20. |
Soriano, F.,
R. Fernandez-Roblas,
R. Calvo, and G. Garcia-Calvo.
1998.
In vitro susceptibilities of aerobic and facultative non-spore-forming gram-positive bacilli to HMR 3647 (RU 66647) and 14 other antimicrobials.
Antimicrob. Agents Chemother.
42:1028-1033 |
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