The mutant-prevention concentration (MPC) : ideas for restricting the development of fluoroquinolone resistance
Hansen, Glen Thomas
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 Pseudomonas aeruginosa, 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 Citrobacter freundii, Enterobacter cloacae, Escherichia. coli, Klebsiella pneumoniae, P. aeruginosa, and Streptococus pneumoniae. Against clinical isolates of S. pneumoniae, 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 S. pneumoniae. MPC90 results for 155 clinical isolates of P. aeruginosa against ciprofloxacin and levofloxacin were 4 and 16 ƒÝg/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 C. freundii (n=20), E. cloacae (n=20), E. coli (n=20), K. pneumoniae (n=20), and P. aeruginosa (n=20) for ciprofloxacin, levofloxacin and garenoxacin. MPC results were 2-to-8 fold higher than MIC or MBC results. Ciprofloxacin MPC results for E.coli, C. freundii, E. cloacae, K. pneumoniae, and P. aeruginosa were 0.5, 2, 1, 1, and 4 ƒÝg/ml, respectively. Levofloxacin, MPC results were were 1, 2, 4, 1, and 16 ƒÝg/ml, respectively. Garenoxacin, MPC were 1, 8, >8, 4, and >32 ƒÝg/ml, respectively. Garenoxacin had the highest MIC and MPC results and was the least active compound tested against isolates of C. freundii, E. cloacae, and P. aeruginosa. 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.
DegreeDoctor of Philosophy (Ph.D.)
DepartmentMicrobiology and Immunology
ProgramMicrobiology and Immunology
CommitteeZiola, Barry; Sanche, Steve; Potter, Andrew A.; Howard, S. Peter; Doern, Gary; Deneer, Harry
Copyright DateMarch 2005