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Antimicrobial Agents and Chemotherapy, February 2001, p. 624-626, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.624-626.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

In Vitro Activities of the New Ketolide HMR 3647 (Telithromycin) in Comparison with Those of Eight Other Antibiotics against Viridans Group Streptococci Isolated from Blood of Neutropenic Patients with Cancer

Fernando Alcaide,1,* Miguel Angel Benítez,1 Jordi Carratalà,2 Francesc Gudiol,2 Josefina Liñares,1 and Rogelio Martín1

Departments of Microbiology1 and Infectious Diseases,2 Hospital "Prínceps d'Espanya," Ciutat Sanitària i Universitària de Bellvitge, 08907 L'Hospitalet de Llobregat, Barcelona, Spain

Received 12 June 2000/Returned for modification 18 October 2000/Accepted 7 November 2000


    ABSTRACT
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Abstract
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The in vitro activities of the ketolide telithromycin and eight other antibiotics were tested against 77 strains of viridans group streptococci isolated from blood samples of neutropenic patients. Thirty-one (40.3%) of the strains were resistant to penicillin G, and 27 (35.1%) were resistant to erythromycin A. Telithromycin (MIC range of <= 0.03 to 1 µg/ml) was the most active antimicrobial tested. These data suggest that telithromycin could be useful for treatment of viridans group streptococcal bacteremia in neutropenic patients with cancer.


    TEXT
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Viridans group streptococci are now recognized as a major cause of bacteremia in neutropenic patients with cancer (3, 11, 12, 16). Importantly, viridans group streptococcal bacteremia may be complicated by hypotension, septic shock, and adult respiratory distress syndrome, which have a high mortality rate (5, 7, 18, 29). Oral penicillin V or roxythromycin added to a fluoroquinolone have resulted in significant reductions of viridans group streptococcal bacteremia (20, 22). However, the increasing incidence of isolation of viridans group streptococci resistant to penicillin and macrolides compromises the current utility of these antibiotics (1, 2, 9, 14, 30). Indeed, there have been reports of bacteremias due to penicillin-resistant strains developing in patients receiving prophylaxis with a combination of quinolone and penicillin (7; V. Krcmery and J. Trupl, Letter, Lancet 346:1362-1363, 1995). On the other hand, the emergence of strains of viridans group streptococci resistant to multiple antibiotics has complicated the treatment of infections caused by these organisms. Thus, there is a need for antimicrobial agents against viridans group streptococci.

HMR 3647 (telithromycin) is a new, semisynthetic 14-membered-ring agent belonging to a new chemical family, the ketolides, which have shown promising in vitro activity against a range of microorganisms (4, 15, 19, 23, 26, 28).

The aim of this study was to compare the susceptibilities to telithromycin of 77 viridans group streptococci isolated consecutively from blood samples of neutropenic patients with cancer with their susceptibilities to eight other antibiotics, in order to determine the potential of telithromycin against these organisms.

(This study was partially presented at the 9th European Congress of Clinical Microbiology and Infectious Diseases, Berlin, Germany, March 1999 [F. Alcaide, M. A. Benítez, J. Carratalà, F. Gudiol, J. Liñares, and R. Martín, abstr. P174, p. 131].)

A total of 77 strains of viridans group streptococci isolated from the blood samples of adult neutropenic patients with cancer (<500 granulocytes/mm3) were tested for antimicrobial susceptibilities. Only one isolate per patient was tested. Alpha-hemolytic and nonhemolytic streptococci were identified to species level according to standard methods (27). Colony morphology was evaluated, and pure cultures were tested for production of acid from trehalose, sorbitol, lactose, mannitol, sucrose, inulin, raffinose, glycerol, arabinose, maltose, and sorbose. Isolates were additionally tested for reaction in esculin agar and bile esculin agar, growth in 6.5% sodium chloride broth, ammonia production from arginine, pyruvate utilization, sodium hippurate hydrolysis, and hydrolysis of starch. We used the taxonomy and nomenclature system proposed by Coykendall (13) and updated by Bruckner and Colonna (8), which includes five groups: Streptococcus mitis, S. sanguis, S. milleri, S. salivarius, and S. mutans.

The following antibiotics were tested: HMR 3647 (telithromycin; Hoechst-Marion-Roussel, Romainville, France); penicillin G (C.E.P.A., S.A., Madrid, Spain); cefotaxime (Roussel Ibérica S.A., Madrid, Spain); erythromycin A (Abbott Laboratories, North Chicago, Ill.); clindamycin (Pharmacia & Upjohn, Barcelona, Spain); vancomycin (Eli Lilly & Co., Indianapolis, Ind.); chloramphenicol and co-trimoxazole (Sigma-Aldrich Quimica, S.A., Madrid, Spain); and ciprofloxacin (Bayer, West Haven, Conn.). For each antibiotic, the MIC was determined by the microdilution method, using cation-adjusted Mueller-Hinton broth supplemented with lysed horse blood (final concentration, 2.5%) as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (24). The inoculum was prepared by suspending several colonies from an overnight blood agar culture in sterile 0.9% saline and adjusting the turbidity to 0.5 McFarland standard. The suspension was further diluted to provide a final concentration of bacteria of 5 × 105 CFU/ml in each well of the microdilution trays. The plates were covered with plastic tape and incubated at 35°C for 20 to 24 h. The MIC was defined as the lowest concentration of antibiotic which inhibited visible growth. Strains were classified for erythromycin A and penicillin G susceptibilities according to NCCLS criteria (25). Streptococcus pneumoniae ATCC 49619, Staphylococcus aureus ATCC 29213, and Enterococcus faecalis ATCC 29212 were used for quality control.

The distribution of viridans group streptococci for species isolated was 60 S. mitis strains, 6 S. sanguis strains, 6 S. salivarius strains, 4 S. milleri strains, and 1 S. mutans strain.

The susceptibility testing results are shown in Tables 1 and 2. Thirty-one (40.3%) of the 77 viridans group streptococcal isolates showed decreased susceptibility to penicillin G (MIC range, 0.25 to 16 µg/ml), 13 (16.9%) were intermediately resistant, and 18 (23.4%) were highly resistant. The strains were classified in two groups according to their erythromycin A susceptibility: 50 (64.9%) were susceptible, and 27 (35.1%) were resistant; 26% of the erythromycin-susceptible strains and 66.7% of the highly resistant strains were penicillin resistant (chi-square test, 10.42; P < 0.01).

                              
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  		TABLE 1.   In vitro activities of telithromycin and eight other antibiotics against viridans group streptococci (n = 77) isolated from blood samples of neutropenic cancer patients by erythromycin A susceptibility


                              
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  		TABLE 2.   In vitro activities of telithromycin and eight other antibiotics against viridans group streptococci (n = 77) isolated from blood samples of neutropenic cancer patients by penicillin G susceptibility

S. mitis, in addition to being the most frequently isolated species (77.9%), showed the highest rates of resistance to penicillin G (43.5%) and erythromycin A (38.5%). Regarding the other species, the resistance to penicillin G was found in four of six S. sanguis strains and in one of six S. salivarius strains.

The ketolide telithromycin was the most active antimicrobial tested, followed by vancomycin. All erythromycin-resistant strains were inhibited at 1 µg of telithromycin per ml or less. The MIC at which 50% of the strains were inhibited (MIC50) and MIC90 of telithromycin for these strains were, respectively, 5 and 2 dilutions lower than the MIC50 and MIC90 of erythromycin A. In addition, the MIC50 and MIC90 of this ketolide for intermediately and highly penicillin-resistant strains were <= 0.03 and 0.25 µg/ml, respectively.

The increasing incidence of viridans group streptococcal bacteremia in neutropenic patients observed in many institutions and the emergence of serious complications and resistance to antibiotics are of great concern (6, 17, 21). Our data show that the current rates of penicillin G and erythromycin A resistance among viridans group streptococci isolated from blood samples of neutropenic patients clearly limit the usefulness of these drugs. S. mitis, which is the most frequently isolated species and the one most often linked to the occurrence of complications, shows the highest rate of resistance (9, 10). Our study shows that telithromycin has a good level of in vitro activity against viridans group streptococci, including strains that are highly penicillin G and erythromycin A resistant. According to these findings, telithromycin could be useful for the treatment of viridans group streptococcal bacteremia in neutropenic patients with cancer.


    FOOTNOTES

* Corresponding author. Mailing address: Servei de Microbiologia, Hospital "Princeps d'Espanya," Ciutat Sanitària i Universitària de Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain. Phone: 34-93-2607930. Fax: 34-93-2607547. E-mail: falcaide{at}csub.scs.es.


    REFERENCES
Top
Abstract
Text
References

1. Alcaide, F., J. Liñares, R. Pallares, J. Carratala, M. A. Benitez, F. Gudiol, and R. Martin. 1995. In vitro activities of 22 beta -lactam antibiotics against penicillin-resistant and penicillin-susceptible viridans group streptococci isolated from blood. Antimicrob. Agents Chemother. 39:2243-2247[Abstract].
2. Alcaide, F., J. Carratala, J. Liñares, F. Gudiol, and R. Martin. 1996. In vitro activities of eight macrolide antibiotics and RP-59500 (quinupristin-dalfopristin) against viridans group streptococci isolated from blood of neutropenic cancer patients. Antimicrob. Agents Chemother. 40:2117-2120[Abstract].
3. Awada, A., P. Van der Auwera, P. Meunier, D. Daneau, and J. Klastersky. 1992. Streptococcal and enterococcal bacteremia in patients with cancer. Clin. Infect. Dis. 15:33-48[Medline].
4. 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[Abstract/Free Full Text].
5. Bilgrami, S., J. M. Feingold, D. Dorsky, R. L. Edwards, J. Clive, and P. J. Tutschka. 1998. Streptococcus viridans bacteremia following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 21:591-595[CrossRef][Medline].
6. Bochud, P. Y., T. Calandra, and P. Francioli. 1994. Bacteremia due to viridans streptococci in neutropenic patients: a review. Am. J. Med. 97:256-264[CrossRef][Medline].
7. Bochud, P. Y., P. Eggiman, T. Calandra, G. Van Melle, L. Saghafi, and P. Francioli. 1994. Bacteremia due to viridans streptococcus in neutropenic patients with cancer: clinical spectrum and risk factors. Clin. Infect. Dis. 18:25-31[Medline].
8. Bruckner, D. A., and P. Colonna. 1997. Nomenclature for aerobic and facultative bacteria. Clin. Infect. Dis. 25:1-10[Medline].
9. Carratalà, J., F. Alcaide, A. Fernández-Sevilla, X. Corbella, J. Liñares, and F. Gudiol. 1995. Bacteremia due to viridans streptococci that are highly resistant to penicillin: increase among neutropenic patients with cancer. Clin. Infect. Dis. 20:1169-1173[Medline].
10. Classen, D. C., J. P. Burke, C. D. Ford, S. Evershed, M. R. Aloia, J. K. Wilfahrt, and J. A. Elliott. 1990. Streptococcus mitis sepsis in bone marrow transplant patients receiving oral antimicrobial prophylaxis. Am. J. Med. 89:441-446[CrossRef][Medline].
11. Cometta, A., S. Zinner, R. de Bock, T. Calandra, H. Gaya, J. Klastersky, J. Langenaeken, M. Paesmans, C. Viscoli, M. P. Glauser, and the International Antimicrobial Therapy Cooperative Group of the EORTC. 1995. Piperacillin-tazobactam plus amikacin versus ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. Antimicrob. Agents Chemother. 39:445-452[Abstract/Free Full Text].
12. Cometta, A., T. Calandra, H. Gaya, S. H. Zinner, R. de Bock, A. Del Favero, G. Bucaneve, F. Crokaert, W. V. Kern, J. Klastersky, I. Langenaeken, A. Micozzi, A. Padmos, M. Paesmans, C. Viscoli, M. P. Glauser, and the International Antimicrobial Therapy Cooperative Group of the EORTC and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Infection Program. 1996. Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. Antimicrob. Agents Chemother. 40:1108-1115[Abstract].
13. Coykendall, A. L. 1989. Classification and identification of the viridans streptococci. Clin. Microbiol. Rev. 2:315-328[Abstract/Free Full Text].
14. Doern, G. V., M. J. Ferraro, A. B. Brueggemann, and K. L. Ruoff. 1996. Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States. Antimicrob. Agents Chemother. 40:891-894[Abstract].
15. Goldstein, E. J. C., D. M. Citron, C. V. Merriam, Y. Warren, and K. Tyrrell. 1999. Activities of telithromycin (HMR 3647, RU 66647) compared to those of erythromycin, azithromycin, clarithromycin, roxithromycin, and other antimicrobial agents against unusual anaerobes. Antimicrob. Agents Chemother. 43:2801-2805[Abstract/Free Full Text].
16. González-Barca, E., A. Fernández-Sevilla, J. Carratalà, A. Grañena, and F. Gudiol. 1996. Prospective study of 288 episodes of bacteremia in neutropenic cancer patients in a single institution. Eur. J. Clin. Microbiol. Infect. Dis. 15:291-296[CrossRef][Medline].
17. Guiot, H. F. L., W. G. Peters, P. J. van den Broek, J. W. M. van der Meer, J. A. Kramps, R. Willemze, and R. van Furth. 1990. Respiratory failure elicited by streptococcal septicemia in patients treated with cytosine arabinoside, and its prevention by penicillin. Infection 18:131-137[CrossRef][Medline].
18. Elting, L. S., G. P. Bodey, and B. H. Keefe. 1992. Septicemia and shock syndrome due to viridans streptococci: a case-control study of predisposing factors. Clin. Infect. Dis. 14:1201-1207[Medline].
19. Hoellman, D. B., G. Lin, M. R. Jacobs, and P. C. Appelbaum. 1999. Activity of HMR 3647 compared to those of six compounds against 235 strains of Enterococcus faecalis. Antimicrob. Agents Chemother. 43:166-168[Abstract/Free Full Text].
20. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. 1994. Reduction of fever and streptococcal bacteremia in granulocytopenic patients with cancer. A trial of oral penicillin V or placebo combined with pefloxacin. JAMA 272:1183-1189[Abstract/Free Full Text].
21. Kern, W. V., E. Kurrle, and T. Schmeiser. 1990. Streptococcal bacteremia in adult patients with leukemia undergoing aggressive chemotherapy. A review of 55 cases. Infection 18:138-145[CrossRef][Medline].
22. Kern, W. V., B. Hay, P. Kern, R. Marre, and R. Arnold. 1994. A randomized trial of roxithromycin in patients with acute leukemia and bone marrow transplant recipients receiving fluoroquinolone prophylaxis. Antimicrob. Agents Chemother. 38:465-472[Abstract/Free Full Text].
23. Malathum, K., T. M. Coque, K. V. Singh, and B. E. Murray. 1999. In vitro activities of two ketolides, HMR 3647 and HMR 3004, against gram-positive bacteria. Antimicrob. Agents Chemother. 43:930-936[Abstract/Free Full Text].
24. National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. Approved standard M7-A4. National Committee for Clinical Laboratory Standards, Wayne, Pa.
25. National Committee for Clinical Laboratory Standards. 1999. Performance standards for antimicrobial susceptibility testing: ninth informational supplement. M100-S9. National Committee for Clinical Laboratory Standards, Wayne, Pa.
26. Reinert, R. R., A. Bryskier, and R. Lütticken. 1998. In vitro activities of the new ketolide antibiotics HMR 3004 and HMR 3647 against Streptococcus pneumoniae in Germany. Antimicrob. Agents Chemother. 42:1509-1511[Abstract/Free Full Text].
27. Ruoff, K. L. 1995. Streptococcus, p. 299-307. In P. R. Murray, E. J. Baron, M. A. Pfaller, F. C. Tenover, and R. H. Yolken (ed.), Manual of clinical microbiology, 6th ed. American Society for Microbiology, Washington, D.C.
28. Schülin, T., C. B. Wennersten, R. C. Moellering, Jr., and G. M. Eliopoulos. 1997. In vitro activity of RU 64004, a new ketolide antibiotic, against gram-positive bacteria. Antimicrob. Agents Chemother. 41:1196-1202[Abstract].
29. Steiner, M., J. Villablanca, J. Kersey, N. Ramsay, R. Haake, P. Ferrieri, and D. Weisdorf. 1993. Viridans streptococcal shock in bone marrow transplantation patients. Am. J. Hematol. 42:354-358[Medline].
30. Teng, L. J., P. R. Hsueh, Y. C. Chen, S. W. Ho, and K. T. Luh. 1998. Antimicrobial susceptibility of viridans group streptococci in Taiwan with an emphasis on the high rates of resistance to penicillin and macrolides in Streptococcus oralis. J. Antimicrob. Chemother. 41:621-627[Abstract/Free Full Text].

Antimicrobial Agents and Chemotherapy, February 2001, p. 624-626, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.624-626.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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