The mutant-prevention concentration (MPC) is a novel susceptibility measurement defined by a concentration threshold that would require cells to contain two concurrent resistance mutations for growth. Pneuococcal pneumonia, infections caused by <i> Pseudomonas aeruginosa</i>, and urinary tract infections caused by Gram-negative bacilli represent three distinct clinical situations for which fluoroquinolone-resistance occurs. MPC results were defined and measured for fluoroquinolones against clinical isolates of <i>Citrobacter freundii, Enterobacter cloacae, Escherichia. coli, Klebsiella pneumoniae, P. aeruginosa,</i> and <i> Streptococus pneumoniae</i>. Against clinical isolates of <i>S. pneumoniae</i>, MPC results for six fluoroquinolones were measured. Based on their potential for restricting the selection of resistant mutants, the six fluoroquinolones, in descending order, were found to be gemifloxacin > moxifloxacin > trovafloxacin > gatifloxacin > grepafloxacin > levofloxacin. For several compounds, 90% of clinical isolates that lacked a known resistance mutation had a MPC value that was close to or below the serum levels that could be attained with a dosing regimen recommended by the manufacturers. These data identify gemifloxacin, moxifloxacin and gatifloxacin as good candidates for determining whether MPC can be used as a guide for choosing and eventually administering fluoroquinolones to significantly reduce the development of fluoroquinolone ¡Vresistant <i>S. pneumoniae</i>. MPC90 results for 155 clinical isolates of <i>P. aeruginosa </i>against ciprofloxacin and levofloxacin were 4 and 16 Ýg/ml, respectively. Serum drug concentrations reported previously for standard doses were above MPC90 for 5.5 hr for ciprofloxacin and 0 hr for levofloxacin. These data suggest that superior clinical performance of ciprofloxacin correlates with activity against resistant mutant subpopulations measured in vitro. MPC results were compared with minimum inhibitory concentrations (MIC) measurements preformed by agar dilution, and microbroth dilution and minimal inhibitory concentrations (MBC) for 100 clinical isolates of <i>C. freundii </i> (n=20), <i>E. cloacae</i> (n=20), <i>E. coli</i> (n=20), <i>K. pneumoniae</i> (n=20), and <i>P. aeruginosa</i> (n=20) for ciprofloxacin, levofloxacin and garenoxacin. MPC results were 2-to-8 fold higher than MIC or MBC results. Ciprofloxacin MPC results for <i>E.coli, C. freundii, E. cloacae, K. pneumoniae</i>, and <i>P. aeruginosa</i> were 0.5, 2, 1, 1, and 4 Ýg/ml, respectively. Levofloxacin, MPC results were were 1, 2, 4, 1, and 16 Ýg/ml, respectively. Garenoxacin, MPC were 1, 8, >8, 4, and >32 Ýg/ml, respectively. Garenoxacin had the highest MIC and MPC results and was the least active compound tested against isolates of <i>C. freundii, E. cloacae</i>, and <i>P. aeruginosa</i>. These data support the rational use of quinolones in the treatments of urinary tract infections and suppression of resistance. Incorporation of the MPC measurement into dosing strategies may preserve the longevity of antimicrobial compounds for future infectious diseases.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:SSU.etd-04202005-141823 |
| Date | 22 April 2005 |
| Creators | Hansen, Glen Thomas |
| Contributors | Ziola, Barry, Sanche, Steve, Potter, Andrew A., Howard, S. Peter, Doern, Gary, Deneer, Harry, Blondeau, Joseph |
| Publisher | University of Saskatchewan |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-04202005-141823/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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