Journal of Antimicrobial Chemotherapy (2000) 45, Suppl. S1, 47–49
JAC
In vitro activity of gemifloxacin and other antimicrobial agents against isolates of Bordetella pertussis and Bordetella parapertussis Joel E. Mortensena,b* and Gail L. Rodgersa a
Section of Infectious Diseases, Department of Pediatrics and bDepartment of Pathology and Laboratory Medicine, St Christopher’s Hospital for Children, Philadelphia, PA 19134-1095, USA We investigated the activity of the novel quinolone agent gemifloxacin (SB-265805) and a panel of comparator agents against Bordetella pertussis and Bordetella parapertussis. Erythromycin, azithromycin, ciprofloxacin and gemifloxacin were consistently active against both species. An azithromycin- and erythromycin-resistant B. pertussis isolate was not resistant to any of the other agents tested (gemifloxacin MIC < 0.008 mg/L; ciprofloxacin, < 0.015 mg/L; ampicillin, 2.0 mg/L; trimethoprim–sulphamethoxazole, 4.0 mg/L). The potency of ampicillin, azithromycin, erythromycin, ciprofloxacin and trimethoprim–sulphamethoxazole recorded against B. pertussis and B. parapertussis in this study was comparable to that noted in previous studies. However, MICs were generally higher than those noted in other trials; this may reflect the different methods used. Although in vitro data on the potency of gemifloxacin against B. pertussis and B. parapertussis have not previously been reported, these results are comparable to the potency of other quinolones against these pathogens. Should gemifloxacin achieve similar concentrations within the respiratory tract as other quinolones, this, coupled with its high in vitro potency, suggests that gemifloxacin has potential clinical efficacy in pertussis.
bility data are available for B. pertussis, in vivo efficacy data are lacking. In clinical practice, alternative agents for the treatment of pertussis have to be selected on microbiological and pharmacokinetic criteria since clinical data are not available. The quinolones achieve high concentrations in respiratory secretions.9 Gemifloxacin (SB-265805) is a novel quinolone. This study aimed to determine the in vitro activity of gemifloxacin and comparator agents against B. pertussis and Bordetella parapertussis.
Introduction Erythromycin is the mainstay of antibiotic therapy for pertussis as it decreases the transmission of infection and ameliorates symptoms, particularly in younger, more severely affected infants.1 Many in vitro studies have investigated the potency of other antibiotics against Bordetella spp, in particular the newer macrolides, ampicillin, trimethoprim–sulphamethoxazole, the quinolones and third-generation cephalosporins.2–7 Antimicrobial susceptibility testing of clinical isolates of Bordetella pertussis is not routinely performed owing to the lack of standardization of laboratory methods, the slowly growing and fastidious nature of the organism and, until recently, its universal susceptibility to erythromycin. In 1995, the first erythromycin-resistant B. pertussis isolate (MIC 256 mg/L by Etest) was described in a 2 month-old infant with clinical failure of erythromycin therapy.8 Alternative therapeutic agents are now sought for the treatment of resistant B. pertussis strains, should they become common, and for use in patients unable to tolerate conventional therapy. However, although in vitro suscepti-
Materials and methods Bacterial strains The following bacterial isolates were tested: 102 strains of B. pertussis comprising 99 clinical isolates from patients seen at St Christopher’s Hospital for Children (Philadelphia, PA, USA) collected between 1987 and 1997, reference B. pertussis strains ATCC 8467 and ATCC 9340, and one strain resistant to both erythromycin and azithromycin
*Correspondence address. Department of Pathology and Laboratory Medicine, St Christopher’s Hospital for Children, Erie Avenue at Front Street, Philadelphia, PA 19134-1095, USA. Tel: 1-215-427-5946; Fax: 1-215-427-5511; E-mail:
[email protected]
47 © 2000 The British Society for Antimicrobial Chemotherapy
J. E. Mortenson and G. L. Rodgers obtained from the Centers for Disease Control and Prevention,8 and nine B. parapertussis isolates comprising seven clinical isolates from St Christopher’s Hospital, and B. parapertussis strains ATCC 15311 and ATCC 15989.
concentration of antimicrobial compound at which growth was inhibited.
Results Antimicrobial agents
The activities of the panel of antimicrobial agents against the test strains are presented in the Table. Erythromycin, azithromycin, ciprofloxacin and gemifloxacin were consistently active against both species. The single azithromycinand erythromycin-resistant B. pertussis strain tested was not cross-resistant to any of the other agents tested (gemifloxacin MIC, 0.008 mg/L; ciprofloxacin, 0.015 mg/L; ampicillin, 2.0 mg/L; trimethoprim–sulphamethoxazole, 4.0 mg/L).
Ampicillin, erythromycin, ciprofloxacin, trimethoprim and suphamethoxazole were purchased from Sigma Chemical Co., St Louis, MO, USA. Azithromycin was provided by Pfizer Pharmaceuticals, New York, NY, USA. Gemifloxacin was provided by SmithKline Beecham Pharmaceuticals. Collegeville, PA, USA. Ampicillin, azithromycin, erythromycin, ciprofloxacin and trimethoprim–sulphamethoxazole were tested at concentrations of 0.015–32 mg/L, while gemifloxacin was tested at 0.008–16 mg/L.
MIC determination
Discussion
The assay conditions used in this study were those proposed by Hoppe & Haug in 1988,10 and further developed by Mortensen et al.11 Briefly, the broth microdilution procedure was performed using Mueller–Hinton broth supplemented with 5% lysed horse blood. The inoculum used was a bacterial suspension equivalent to a final density of 5 105 cfu/mL for all isolates, and was confirmed with plate counts. Streptococcus pneumoniae ATCC 49619 was used as the quality control strain since no B. pertussis quality control strain has been validated for susceptibility testing. Microtitre plates were incubated in ambient air for 48 h at 37°C, and the MIC was defined as the lowest
The in vitro activities of ampicillin, azithromycin, erythromycin, ciprofloxacin and trimethoprim–sulphamethoxazole recorded in this study against B. pertussis and B. parapertussis were comparable to those found in previous reports.3,4,6,7 In vitro data on the potency of gemifloxacin against B. pertussis and B. parapertussis have not previously been reported, but these findings are comparable to those of other quinolones which had MIC ranges of 0.03–0.5 mg/L for these pathogens.2,5,6 Should gemifloxacin respiratory tract secretion concentrations prove to be similar to other quinolones, this, coupled with the in vitro potency of gemi-
Table. In vitro activity of test antimicrobial agents against Bordetella spp. MIC (mg/L) Organism (n)/antimicrobial
MIC50
MIC90
range
B. pertussis (102) erythromycin azithromycin ciprofloxacin gemifloxacina ampicillin trimethoprim–sulphamethoxazoleb
0.015 0.015 0.015 0.008 1.0 0.015
0.015 0.015 0.03 0.03 1.0 0.015
0.015–32 0.015–32 0.015–0.06 0.008–0.06 0.25–2.0 0.015–32
B. parapertussis (9) erythromycin azithromycin ciprofloxacin gemifloxacin ampicillin trimethoprim–sulphamethoxazoleb
– – – – – –
– – – – – –
0.125–0.5 0.06–0.125 0.03–0.125 0.003–0.125 8–32 0.25–1
a
Five strains of B. pertussis were not viable for testing against gemifloxacin. Expressed as the MIC of trimethoprim.
b
48
Gemifloxacin against Bordetella spp. 5. Hoppe, J. E. & Simon, C. G. (1990). In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to seven fluoroquinolones. Antimicrobial Agents and Chemotherapy 34, 2287–8.
floxacin against B. pertussis and B. parapertussis, suggests that gemifloxacin could be a future therapeutic option in the treatment of pertussis, particularly in adults who serve as a reservoir for the disease in children.12 Although quinolones are not yet approved for use in children, because of safety concerns, there is growing experience in their use in paediatric patients.13,14 Once quinolone safety data allow more widespread paediatric use, clinical trials will be needed to assess the clinical efficacy of quinolones in children with pertussis.
6. Hoppe, J. E., Dalhoff, A. & Pfrunder, D. (1998). In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to BAY 12-8039, trovafloxacin, and ciprofloxacin. Antimicrobial Agents and Chemotherapy 42, 1868. 7. Kurzyinski, T. A., Boehm, D. M., Rott-Petri, J. A., Schell, R. F. & Allison, P. E. (1988). Antimicrobial susceptibilities of Bordetella species isolated in a Multicenter Pertussis Surveillance Project. Antimicrobial Agents and Chemotherapy 32, 137–40. 8. Lewis, K., Saubolle, M. A., Tenover, F. C., Rudinsky, M. F., Barbour, S. D. & Cherry, J. D. (1995). Pertussis caused by an erythromycin resistant strain of Bordetella pertussis. Pediatric Infectious Disease Journal 14, 338–91.
Acknowledgements The authors acknowledge the technical assistance of Ms Jean Egleton. This work was presented in part at the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, 1998, San Diego, CA.
9. Gerding, D. N. & Hitt, J. A. (1989). Tissue penetration of the new quinolones in humans. Reviews of Infectious Diseases 11, Suppl. 5, S1046–57. 10. Hoppe, J. E. & Haug, A. (1988). Antimicrobial susceptibility of Bordetella pertussis (Part I). Infection 16, 126–30.
References
11. Mortensen, J. E., Rhoads, S. M., Blecker-Shelly, D. & Rodgers, G. L. (1998). A laboratory method for the in vitro susceptibility testing of Bordetella pertussis. In Program and Abstracts of the ThirtyEighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract D-039, p. 138. American Society for Microbiology, Washington, DC.
1. Bass, J. W. (1986). Erythromycin for treatment and prevention of pertussis. Pediatric Infectious Disease 5, 154–7. 2. Appleman, M. E., Hadfield, T. L., Gaines, J. K. & Winn, R. E. (1987). Susceptibility of Bordetella pertussis to five quinolone antimicrobic drugs. Diagnostic Microbiology and Infectious Disease 8, 131–3.
12. Mink, C. M., Cherry, J. D., Christenson, P., Lewis, K., Pineda, E., Shlian, D. et al. (1992). A search for Bordetella pertussis infection in university students. Clinical Infectious Diseases 14, 464–71.
3. Bannatyne, R. M. & Cheung, R. (1982). Antimicrobial susceptibility of Bordetella pertussis strains isolated from 1960 to 1981. Antimicrobial Agents and Chemotherapy 21, 666–7.
13. Redmond, A. O. (1997). Risk–benefit experience of ciprofloxacin use in pediatric patients in the United Kingdom. Pediatric Infectious Disease Journal 16, 147–9.
4. Hoppe, J. E. & Eichhorn, A. (1989). Activity of new macrolides against Bordetella pertussis and Bordetella parapertussis. European Journal of Clinical Microbiology and Infectious Diseases 8, 653–4.
14. Hampel, B., Hullmann, R. & Schmidt, H. (1997). Ciprofloxacin in pediatrics: worldwide clinical experience based compassionate use—safety report. Pediatric Infectious Disease Journal 16, 127–9.
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