Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1990 Jul;34(7):1407–1413. doi: 10.1128/aac.34.7.1407

Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans.

D J Hardy 1, R N Swanson 1, R A Rode 1, K Marsh 1, N L Shipkowitz 1, J J Clement 1
PMCID: PMC175991  PMID: 2143642

Abstract

MICs of clarithromycin and its major human metabolite, 14-hydroxy-clarithromycin, for Haemophilus influenzae in combination were reduced two- to fourfold compared with the MICs of each compound alone. Serum reduced the MICs of the parent compound and metabolite two- to fourfold compared with the MICs in medium without serum. In serum spiked with clinically relevant concentrations of clarithromycin and 14-hydroxy-clarithromycin at a fixed ratio of 4:1, 15 of 16 strains (94%) were inhibited and killed by combinations containing 1.2 and 0.3 micrograms/ml, respectively. In time kill experiments, the combination of parent compound and metabolite at one-fourth and one-half of their individual MICs, respectively, reduced bacterial counts by greater than 5 log CFU. The postantibiotic effect of clarithromycin combined with 14-hydroxy-clarithromycin was twice that of clarithromycin when tested alone. When orally administered to gerbils with H. influenzae otitis media, the 14-hydroxy metabolite was significantly more active than clarithromycin in reducing bacterial counts from the middle ear. The in vivo activity of the two compounds in combination was synergistic or additive, depending on the level of H. influenzae present at the time treatment was initiated. Significant reductions in bacterial counts and increases in cure rates were observed when clarithromycin at 50 or 100 mg/kg of body weight was combined with 14-hydroxy-clarithromycin at 12 mg/kg or higher. Results from in vitro and in vivo combinations suggest that routine susceptibility tests and animal efficacy studies with clarithromycin alone may underestimate its potential efficacy against H. influenzae.

Full text

PDF
1407

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barry A. L., Fernandes P. B., Jorgensen J. H., Thornsberry C., Hardy D. J., Jones R. N. Variability of clarithromycin and erythromycin susceptibility tests with Haemophilus influenzae in four different broth media and correlation with the standard disk diffusion test. J Clin Microbiol. 1988 Nov;26(11):2415–2420. doi: 10.1128/jcm.26.11.2415-2420.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barry A. L., Jones R. N., Thornsberry C. Disk diffusion and disk elution tests with A-56268 and erythromycin. Eur J Clin Microbiol. 1987 Feb;6(1):109–111. doi: 10.1007/BF02097213. [DOI] [PubMed] [Google Scholar]
  3. Bundtzen R. W., Gerber A. U., Cohn D. L., Craig W. A. Postantibiotic suppression of bacterial growth. Rev Infect Dis. 1981 Jan-Feb;3(1):28–37. doi: 10.1093/clinids/3.1.28. [DOI] [PubMed] [Google Scholar]
  4. Fernandes P. B., Bailer R., Swanson R., Hanson C. W., McDonald E., Ramer N., Hardy D., Shipkowitz N., Bower R. R., Gade E. In vitro and in vivo evaluation of A-56268 (TE-031), a new macrolide. Antimicrob Agents Chemother. 1986 Dec;30(6):865–873. doi: 10.1128/aac.30.6.865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fernandes P. B., Hardy D., Bailer R., McDonald E., Pintar J., Ramer N., Swanson R., Gade E. Susceptibility testing of macrolide antibiotics against Haemophilus influenzae and correlation of in vitro results with in vivo efficacy in a mouse septicemia model. Antimicrob Agents Chemother. 1987 Aug;31(8):1243–1250. doi: 10.1128/aac.31.8.1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fernandes P. B., Ramer N., Rode R. A., Freiberg L. Bioassay for A-56268 (TE-031) and identification of its major metabolite, 14-hydroxy-6-O-methyl erythromycin. Eur J Clin Microbiol Infect Dis. 1988 Feb;7(1):73–76. doi: 10.1007/BF01962181. [DOI] [PubMed] [Google Scholar]
  7. Fernandes P. B., Swanson R. N., Hardy D. J., McDonald E. J., Ramer N. Effect of dosing intervals on efficacy of clarithromycin and erythromycin in mouse infection models. Drugs Exp Clin Res. 1988;14(7):441–444. [PubMed] [Google Scholar]
  8. Fulghum R. S., Brinn J. E., Smith A. M., Daniel H. J., 3rd, Loesche P. J. Experimental otitis media in gerbils and chinchillas with Streptococcus pneumoniae, Haemophilus influenzae, and other aerobic and anaerobic bacteria. Infect Immun. 1982 May;36(2):802–810. doi: 10.1128/iai.36.2.802-810.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hanson C. W., Bailer R., Gade E., Rode R. A., Fernandes P. B. Regression analysis, proposed interpretative zone size standards, and quality control guidelines for a new macrolide antimicrobial agent, A-56268 (TE-031). J Clin Microbiol. 1987 Jun;25(6):1079–1082. doi: 10.1128/jcm.25.6.1079-1082.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hardy D. J., Hensey D. M., Beyer J. M., Vojtko C., McDonald E. J., Fernandes P. B. Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides. Antimicrob Agents Chemother. 1988 Nov;32(11):1710–1719. doi: 10.1128/aac.32.11.1710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jones R. N. A review of cephalosporin metabolism: a lesson to be learned for future chemotherapy. Diagn Microbiol Infect Dis. 1989 Jan-Feb;12(1):25–31. doi: 10.1016/0732-8893(89)90042-4. [DOI] [PubMed] [Google Scholar]
  12. Jorgensen J. H., Redding J. S., Maher L. A., Howell A. W. Improved medium for antimicrobial susceptibility testing of Haemophilus influenzae. J Clin Microbiol. 1987 Nov;25(11):2105–2113. doi: 10.1128/jcm.25.11.2105-2113.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pearson R. D., Steigbigel R. T., Davis H. T., Chapman S. W. Method of reliable determination of minimal lethal antibiotic concentrations. Antimicrob Agents Chemother. 1980 Nov;18(5):699–708. doi: 10.1128/aac.18.5.699. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES