Mutant Prevention Concentration of Gemifloxacin for Clinical Isolates of Streptococcus pneumoniae
LETTER#1\$'7, 百拇医药
Fluoroquinolone resistance is beginning to appear among isolates of Streptococcus pneumoniae (4, 7, 8, 10). We have argued that resistance arises as a consequence of dosing that places tissue concentrations between the MIC and the mutant prevention concentration (MPC), a new measure of activity related to the MIC of the least susceptible, single-step mutant (15, 16). If this is true, MPC can be used to identify fluoroquinolones that are least likely to selectively enrich resistant subpopulations. We previously estimated MPC for several fluoroquinolones with about 100 clinical isolates of S. pneumoniae obtained from the Royal University Hospital, Saskatoon, Canada (2). We now add gemifloxacin to the list of compounds compared and increase the number of isolates tested to 146 for all of the compounds.#1\$'7, 百拇医药
Table 1 lists MICs and MPCs for gemifloxacin, moxifloxacin, gatifloxacin, and levofloxacin determined as described previously (2) using the same set of isolates for each compound. Fluoroquinolone-resistant isolates were excluded. Gemifloxacin had the lowest modal MPC (0.25 µg/ml), followed by moxifloxacin (0.5 µg/ml), gatifloxacin (1 µg/ml), and levofloxacin (2 µg/ml). The same rank order was observed when MPC was determined for 90% of the isolates. These data are consistent with gemifloxacin having more activity than the other compounds against resistant mutants (9, 14). When the MIC at which 90% of the susceptible isolates are inhibited (MIC90) was determined, gemifloxacin was also more active than moxifloxacin, gatifloxacin, and levofloxacin in these comparisons by 2, 3, and 4 dilutions, respectively.
fig.ommitteedh|es, 百拇医药
TABLE 1. Fluoroquinolone activity with clinical isolates of S. pneumoniaeah|es, 百拇医药
Since the effectiveness of an antibacterial agent is likely to be a function of both activity (MIC and MPC) and pathogen exposure (5, 11), comparision of compounds requires consideration of drug pharmacokinetics in human tissues. From published values of concentrations in serum, we calculated the time above MPC for each compound when dosed as recommended by the manufacturer. Moxifloxacin is expected to have a concentration in serum above the MPC at which 90% of the isolates tested are prevented (MPC90) for 18 h. For gemifloxacin, gatifloxacin, and levofloxacin, those times are 4, 1 to 2, and 0 h, respectively. This suggests that moxifloxacin may be the most effective at restricting the development of resistance, even though gemifloxacin has the lowest MIC and MPC.h|es, 百拇医药
Table 1 also lists values of the area under the concentration-time curve from 0 to 24 h/MIC and the maximum concentration of drug in serum (Cmax)/MIC for recommended doses. For both parameters gemifloxacin exhibits higher values than moxifloxacin. If these two parameters are inversely related to the selection of resistant mutants (1, 6, 13), resistance should develop less often from treatment with gemifloxacin than with moxifloxacin. But time above MPC (Table 1) and low-concentration cycling (12) predict the opposite outcome. A clinical comparison of these two compounds may help distinguish between MPC-based ideas (15) and empirical pharmacodynamics (6, 13) for predicting the development of resistance. Such a comparison is important because neither method can be easily tested: MPC is an in vitro measure that does not take into account compartments in patients where drug concentrations and bacterial growth properties are poorly defined, and pharmacodynamic methods require examining very large numbers of patients to identify the point at which the overall prevalence of resistance does not increase.
ACKNOWLEDGMENTSrw1|)#, 百拇医药
We thank S. Boros for technical assistance and D. Leciuk for clerical support.rw1|)#, 百拇医药
The work was funded in part by unrestricted grants from GlaxoSmithKline and Bayer AG and by National Institutes of Health grant AI 35257.rw1|)#, 百拇医药
REFERENCESrw1|)#, 百拇医药
Blaser, J., B. Stone, M. Groner, and S. Zinner. 1987. Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance. Antimicrob. Agents Chemother. 31:1054-1060.rw1|)#, 百拇医药
Blondeau, J. M., X. Zhao, G. Hansen, and K. Drlica. 2001. Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45:433-438.rw1|)#, 百拇医药
Blondeau, J. M., K. Drlica, G. Hansen, and X. Zhao. 2001. The relationship between the mutant prevention concentration (MPC) of fluoroquinolones (FQ) against Streptococcus pneumoniae (SP) and the 24 hour dose response curves, abstr. P71. In Program Abstr. Seventh International Symposium on New Quinolones, Edinburgh, Scotland.
Chen, D. K., A. McGeer, J. C. de Azavedo, D. E. Low, et al. 1999. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N. Engl. J. Med. 341:233-239.+gn, http://www.100md.com
Craig, W. 1998. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 26:1-12.+gn, http://www.100md.com
Drusano, G. L., D. Johnson, M. Rosen, and H. Standiford. 1993. Pharmacodynamics of a fluoroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas sepsis. Antimicrob. Agents Chemother. 37:483-490.+gn, http://www.100md.com
Ho, P., R. Yung, D. Tsang, T. Que, M. Ho, W. Seto, T. Ng, W. Yam, and W. Ng. 2001. Increasing resistance of Streptococcus pneumoniae to fluoroquinolones: results of a Hong Kong multicentre study in 2000. J. Antimicrob. Chemother. 48:659-665.+gn, http://www.100md.com
Nagai, K., P. C. Appelbaum, T. A. Davies, L. M. Kelly, D. B. Hoellman, A. T. Andrasevic, L. Drukalska, W. Hryniewicz, M. R. Jacobs, J. Kolman, J. Miciuleviciene, M. Pana, L. Setchanova, M. K. Thege, H. Hupkova, J. Trupl, and P. Urbaskova. 2002. Susceptibilities to telithromycin and six other agents and prevalence of macrolide resistance due to L4 ribosomal protein mutation among 992 pneumococci from 10 Central and Eastern European countries. Antimicrob. Agents Chemother. 46:371-377.
Nagai, K., T. Davies, B. Dewasse, M. Jacobs, and P. Appelbaum. 2001. Single- and multi-step resistance selection study of gemifloxacin compared with trovafloxacin, ciprofloxacin, gatifloxacin, and moxifloxacin in Streptococcus pneumoniae. J. Antimicrob. Chemother. 48:365-374.;hju^, 百拇医药
Quale, J., D. Landman, J. Ravishankar, C. Flores, and S. Bratu. 2002. Streptococcus pneumoniae, Brooklyn, New York: fluoroquinolone resistance at our doorstep. Emerg. Infect. Dis. 8:594-597.;hju^, 百拇医药
Schentag, J. J., K. K. Gilliland, and J. A. Paladino. 2001. What have we learned from pharmacokinetic and pharmacodynamic theories? Clin. Infect. Dis. 32(Suppl. 1):S39-S46.;hju^, 百拇医药
Schmitz, F.-J., M. Boos, S. Mayer, D. Hafner, H. Jagusch, J. Verhoef, and A. C. Fluit. 2001. Propensity of fluoroquinolones with different moieties at position 8 to cause resistance development in clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45:2666-2667.;hju^, 百拇医药
Thomas, J., A. Forrest, S. Bhavnani, J. Hyatt, A. Cheng, C. Ballow, and J. Schentag. 1998. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob. Agents Chemother. 42:521-527.;hju^, 百拇医药
Urban, C., N. Rahman, X. Zhao, N. Mariano, S. Segal-Maurer, K. Drlica, and J. Rahal. 2001. Fluoroquinolone-resistant Streptococcus pneumoniae associated with levofloxacin therapy. J. Infect. Dis. 184:794-798.;hju^, 百拇医药
Zhao, X., and K. Drlica. 2001. Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin. Infect. Dis. 33(Suppl. 3):S147-S156.;hju^, 百拇医药
Zhao, X., and K. Drlica. 2002. Restricting the selection of antibiotic-resistant mutants: measurement and potential uses of the mutant selection window. J. Infect. Dis. 185:561-565.(Prevention)
Fluoroquinolone resistance is beginning to appear among isolates of Streptococcus pneumoniae (4, 7, 8, 10). We have argued that resistance arises as a consequence of dosing that places tissue concentrations between the MIC and the mutant prevention concentration (MPC), a new measure of activity related to the MIC of the least susceptible, single-step mutant (15, 16). If this is true, MPC can be used to identify fluoroquinolones that are least likely to selectively enrich resistant subpopulations. We previously estimated MPC for several fluoroquinolones with about 100 clinical isolates of S. pneumoniae obtained from the Royal University Hospital, Saskatoon, Canada (2). We now add gemifloxacin to the list of compounds compared and increase the number of isolates tested to 146 for all of the compounds.#1\$'7, 百拇医药
Table 1 lists MICs and MPCs for gemifloxacin, moxifloxacin, gatifloxacin, and levofloxacin determined as described previously (2) using the same set of isolates for each compound. Fluoroquinolone-resistant isolates were excluded. Gemifloxacin had the lowest modal MPC (0.25 µg/ml), followed by moxifloxacin (0.5 µg/ml), gatifloxacin (1 µg/ml), and levofloxacin (2 µg/ml). The same rank order was observed when MPC was determined for 90% of the isolates. These data are consistent with gemifloxacin having more activity than the other compounds against resistant mutants (9, 14). When the MIC at which 90% of the susceptible isolates are inhibited (MIC90) was determined, gemifloxacin was also more active than moxifloxacin, gatifloxacin, and levofloxacin in these comparisons by 2, 3, and 4 dilutions, respectively.
fig.ommitteedh|es, 百拇医药
TABLE 1. Fluoroquinolone activity with clinical isolates of S. pneumoniaeah|es, 百拇医药
Since the effectiveness of an antibacterial agent is likely to be a function of both activity (MIC and MPC) and pathogen exposure (5, 11), comparision of compounds requires consideration of drug pharmacokinetics in human tissues. From published values of concentrations in serum, we calculated the time above MPC for each compound when dosed as recommended by the manufacturer. Moxifloxacin is expected to have a concentration in serum above the MPC at which 90% of the isolates tested are prevented (MPC90) for 18 h. For gemifloxacin, gatifloxacin, and levofloxacin, those times are 4, 1 to 2, and 0 h, respectively. This suggests that moxifloxacin may be the most effective at restricting the development of resistance, even though gemifloxacin has the lowest MIC and MPC.h|es, 百拇医药
Table 1 also lists values of the area under the concentration-time curve from 0 to 24 h/MIC and the maximum concentration of drug in serum (Cmax)/MIC for recommended doses. For both parameters gemifloxacin exhibits higher values than moxifloxacin. If these two parameters are inversely related to the selection of resistant mutants (1, 6, 13), resistance should develop less often from treatment with gemifloxacin than with moxifloxacin. But time above MPC (Table 1) and low-concentration cycling (12) predict the opposite outcome. A clinical comparison of these two compounds may help distinguish between MPC-based ideas (15) and empirical pharmacodynamics (6, 13) for predicting the development of resistance. Such a comparison is important because neither method can be easily tested: MPC is an in vitro measure that does not take into account compartments in patients where drug concentrations and bacterial growth properties are poorly defined, and pharmacodynamic methods require examining very large numbers of patients to identify the point at which the overall prevalence of resistance does not increase.
ACKNOWLEDGMENTSrw1|)#, 百拇医药
We thank S. Boros for technical assistance and D. Leciuk for clerical support.rw1|)#, 百拇医药
The work was funded in part by unrestricted grants from GlaxoSmithKline and Bayer AG and by National Institutes of Health grant AI 35257.rw1|)#, 百拇医药
REFERENCESrw1|)#, 百拇医药
Blaser, J., B. Stone, M. Groner, and S. Zinner. 1987. Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance. Antimicrob. Agents Chemother. 31:1054-1060.rw1|)#, 百拇医药
Blondeau, J. M., X. Zhao, G. Hansen, and K. Drlica. 2001. Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45:433-438.rw1|)#, 百拇医药
Blondeau, J. M., K. Drlica, G. Hansen, and X. Zhao. 2001. The relationship between the mutant prevention concentration (MPC) of fluoroquinolones (FQ) against Streptococcus pneumoniae (SP) and the 24 hour dose response curves, abstr. P71. In Program Abstr. Seventh International Symposium on New Quinolones, Edinburgh, Scotland.
Chen, D. K., A. McGeer, J. C. de Azavedo, D. E. Low, et al. 1999. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N. Engl. J. Med. 341:233-239.+gn, http://www.100md.com
Craig, W. 1998. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 26:1-12.+gn, http://www.100md.com
Drusano, G. L., D. Johnson, M. Rosen, and H. Standiford. 1993. Pharmacodynamics of a fluoroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas sepsis. Antimicrob. Agents Chemother. 37:483-490.+gn, http://www.100md.com
Ho, P., R. Yung, D. Tsang, T. Que, M. Ho, W. Seto, T. Ng, W. Yam, and W. Ng. 2001. Increasing resistance of Streptococcus pneumoniae to fluoroquinolones: results of a Hong Kong multicentre study in 2000. J. Antimicrob. Chemother. 48:659-665.+gn, http://www.100md.com
Nagai, K., P. C. Appelbaum, T. A. Davies, L. M. Kelly, D. B. Hoellman, A. T. Andrasevic, L. Drukalska, W. Hryniewicz, M. R. Jacobs, J. Kolman, J. Miciuleviciene, M. Pana, L. Setchanova, M. K. Thege, H. Hupkova, J. Trupl, and P. Urbaskova. 2002. Susceptibilities to telithromycin and six other agents and prevalence of macrolide resistance due to L4 ribosomal protein mutation among 992 pneumococci from 10 Central and Eastern European countries. Antimicrob. Agents Chemother. 46:371-377.
Nagai, K., T. Davies, B. Dewasse, M. Jacobs, and P. Appelbaum. 2001. Single- and multi-step resistance selection study of gemifloxacin compared with trovafloxacin, ciprofloxacin, gatifloxacin, and moxifloxacin in Streptococcus pneumoniae. J. Antimicrob. Chemother. 48:365-374.;hju^, 百拇医药
Quale, J., D. Landman, J. Ravishankar, C. Flores, and S. Bratu. 2002. Streptococcus pneumoniae, Brooklyn, New York: fluoroquinolone resistance at our doorstep. Emerg. Infect. Dis. 8:594-597.;hju^, 百拇医药
Schentag, J. J., K. K. Gilliland, and J. A. Paladino. 2001. What have we learned from pharmacokinetic and pharmacodynamic theories? Clin. Infect. Dis. 32(Suppl. 1):S39-S46.;hju^, 百拇医药
Schmitz, F.-J., M. Boos, S. Mayer, D. Hafner, H. Jagusch, J. Verhoef, and A. C. Fluit. 2001. Propensity of fluoroquinolones with different moieties at position 8 to cause resistance development in clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45:2666-2667.;hju^, 百拇医药
Thomas, J., A. Forrest, S. Bhavnani, J. Hyatt, A. Cheng, C. Ballow, and J. Schentag. 1998. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob. Agents Chemother. 42:521-527.;hju^, 百拇医药
Urban, C., N. Rahman, X. Zhao, N. Mariano, S. Segal-Maurer, K. Drlica, and J. Rahal. 2001. Fluoroquinolone-resistant Streptococcus pneumoniae associated with levofloxacin therapy. J. Infect. Dis. 184:794-798.;hju^, 百拇医药
Zhao, X., and K. Drlica. 2001. Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin. Infect. Dis. 33(Suppl. 3):S147-S156.;hju^, 百拇医药
Zhao, X., and K. Drlica. 2002. Restricting the selection of antibiotic-resistant mutants: measurement and potential uses of the mutant selection window. J. Infect. Dis. 185:561-565.(Prevention)