Activity of ketoconazole against and in the mouse model Free

Abstract

There is an urgent need for the development of new drugs that are active against drug-resistant strains and can shorten tuberculosis (TB) therapy. It has previously been reported that the azole class of antifungals has anti-TB activity . This study evaluated ketoconazole (KTC) for activity against . The MIC of KTC for different strains ranged from 8 to 16 μg ml under both acidic and neutral conditions, with the minimum bactericidal concentration being about twofold higher than the MIC. KTC had enhanced activity against old, non-growing bacilli when combined with pyrazinamide (PZA) and rifampicin (RIF). A single oral dose of KTC at 75 mg kg led to an inhibitory serum concentration 2 h after administration. The activity of KTC was evaluated in established pulmonary TB in the murine model, compared alone and in combination with isoniazid (INH), PZA and RIF. KTC alone exhibited little effect after short-term treatment, with a borderline bacteriostatic effect on spleen colony counts but not on lung counts. KTC, when added in combination with INH, PZA and RIF, significantly improved the treatment outcome in the lungs (compared with treatment with INH, PZA and RIF). The lowest numbers of bacilli in lungs were found in mice treated with KTC, PZA and RIF. Further investigation is necessary to determine the role of KTC in the treatment of TB.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.47058-0
2007-08-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jmm/56/8/1047.html?itemId=/content/journal/jmm/10.1099/jmm.0.47058-0&mimeType=html&fmt=ahah

References

  1. American Thoracic Society, CDC & Infectious Diseases Society of America; 2003; Treatment of tuberculosis. MMWR Recomm Rep 52:RR111–77
    [Google Scholar]
  2. Boshoff H. I., Myers T. G., Copp B. R., McNeil M. R., Wilson M. A., Barry C. E. III 2004; The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem 279:40174–40184 [CrossRef]
    [Google Scholar]
  3. Engelhard D., Stutman H. R., Marks M. I. 1984; Interaction of ketoconazole with rifampin and isoniazid. N Engl J Med 311:1681–1683 [CrossRef]
    [Google Scholar]
  4. Finch C. K., Chrisman C. R., Baciewicz A. M., Self T. H. 2002; Rifampin and rifabutin drug interactions: an update. Arch Intern Med 162:985–992 [CrossRef]
    [Google Scholar]
  5. Grosset J., Truffot-Pernot C., Lacroix C., Ji B. 1992; Antagonism between isoniazid and the combination pyrazinamide-rifampin against tuberculosis infection in mice. Antimicrob Agents Chemother 36:548–551 [CrossRef]
    [Google Scholar]
  6. McCune R., Lee S. H., Deuschle K., McDermott W. 1957; Ineffectiveness of izoniazid in modifying the phenomenon of microbial persistence. Am Rev Tuberc 76:1106–1109
    [Google Scholar]
  7. McLean K. J., Marshall K. R., Richmond A., Hunter I. S., Fowler K., Kieser T., Gurcha S. S., Besra G. S., Munro A. W. 2002; Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes. Microbiology 148:2937–2949
    [Google Scholar]
  8. NCCLS 1999 Methodology for the Serum Bactericidal Test; Approved Guideline . NCCLS document M21-A Wayne, PA: National Committee for Clinical Laboratory Standards;
    [Google Scholar]
  9. Nuermberger E. L., Yoshimatsu T., Tyagi S., O'Brien R. J., Vernon A. N., Chaisson R. E., Bishai W. R., Grosset J. H. 2004; Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med 169:421–426 [CrossRef]
    [Google Scholar]
  10. Sun Z., Zhang Y. 1999; Antituberculosis activity of certain antifungal and antihelmintic drugs. Tuber Lung Dis 79:319–320 [CrossRef]
    [Google Scholar]
  11. Zhang Y., Permar S., Sun Z. 2002; Conditions that may affect the results of Mycobacterium tuberculosis susceptibility testing to pyrazinamide. J Med Microbiol 51:42–49
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.47058-0
Loading
/content/journal/jmm/10.1099/jmm.0.47058-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed