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Antimicrobial Agents and Chemotherapy, January 2006, p. 403-404, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.403-404.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Low Correlation between MIC and Mutant Prevention Concentration


   LETTER
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References
 
Soon after the term mutant prevention concentration (MPC) was coined to define the MIC of the least susceptible mutant subpopulation of a microbial culture (2), we noticed that MPCs and MICs correlated poorly (r2 = 0.39) for a set of closely related fluoroquinolones when determined with Mycobacterium smegmatis (9). Subsequently, isolated examples were described in which correlation was low for a variety of fluoroquinolones with strains of Escherichia coli, Salmonella enterica, and Staphylococcus aureus (5, 8, 10), and a set of 20 clinical isolates of E. coli showed a low correlation (r2 = 0.58) for ciprofloxacin (6). To determine whether a low correlation between MICs and MPCs is likely to be a general phenomenon, we calculated the correlation coefficients for several quinolones with five bacterial species and for three macrolides with Streptococcus pneumoniae using data from published and unpublished studies of clinical isolates. As shown in Table 1, r2,determined by linear regression, was below 0.5 for fluoroquinolones with E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, S. aureus, and S. pneumoniae (an exception was levofloxacin with K. pneumoniae [r2 = 0.7]). Values of r2 were slightly above 0.5 for three macrolides with S. pneumoniae (Table 1).


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  		TABLE 1. Relationship between MICs and MPCs

 
Low correlations between MICs and MPCs with clinical isolates are likely to require a complex explanation. These isolates probably contain mutant subpopulations that vary considerably in relative abundance and drug susceptibility, which will contribute to a wide variation in MICs when the mutants are abundant enough to be scored. The isolates may also contain many different multistep mutants (1) which may or may not represent the least susceptible subpopulations that determine MPCs. Added complexity derives from some resistance mutations having a much larger effect on MPCs than on MICs (4). Indeed, isolates with the same MIC were found to have values of MPC that ranged over 5 twofold dilutions.

A consequence of a low correlation between MICs and MPCs is that MPCs cannot be estimated accurately from MICs on an individual patient basis. Thus, using antimutant strategies for individual patients will require measurement of the MPC. Likewise, empirical estimates of antimutant activity that are keyed to MIC-based pharmacokinetic-pharmacodynamic indices, such as area under the concentration-time curve at 24 h/MIC, will tend to exhibit more patient-to-patient variability than indices using MPCs.


   ACKNOWLEDGMENTS
 
We thank Marila Gennaro and Richard Pine for critical comments on the manuscript.

The work was supported in part by NIH grant AI35257.


   REFERENCES
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 References
 

  1. Campion, J. J., P. J. McNamara, and M. E. Evans. 2004. Evolution of ciprofloxacin-resistant Staphylococcus aureus in in vitro pharmacokinetic environments. Antimicrob. Agents Chemother. 48:4733-4744.[Abstract/Free Full Text]
  2. Dong, Y., X. Zhao, J. Domagala, and K. Drlica. 1999. Effect of fluoroquinolone concentration on selection of resistant mutants of Mycobacterium bovis BCG and Staphylococcus aureus. Antimicrob. Agents Chemother. 43:1756-1758.[Abstract/Free Full Text]
  3. Hansen, G. T., K. Metzler, K. Drlica, and J. M. Blondeau. 2003. Mutant prevention concentration of gemifloxacin for clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 47:440-441.[Free Full Text]
  4. Li, X., X. Zhao, and K. Drlica. 2002. Selection of Streptococcus pneumoniae mutants having reduced susceptibility to moxifloxacin and levofloxacin. Antimicrob. Agents Chemother. 46:522-524.[Abstract/Free Full Text]
  5. Linde, H.-J., and N. Lehn. 2004. Mutant prevention concentration of nalidixic acid, ciprofloxacin, clinafloxacin, levofloxacin, norfloxacin, ofloxacin, sparfloxacin or trovafloxacin for Escherichia coli under different growth conditions. J. Antimicrob. Chemother. 53:252-257.[Abstract/Free Full Text]
  6. Marcusson, L., S. Olofsson, P. Lindgren, O. Cars, and D. Hughes. 2005. Mutant prevention concentration of ciprofloxacin for urinary tract infection isolates of Escherichia coli. J. Antimicrob. Chemother. 55:938-943.[Abstract/Free Full Text]
  7. Metzler, K., G. Hansen, P. Hedlin, E. Harding, K. Drlica, and J. Blondeau. 2004. Comparison of minimal inhibitory and mutant prevention concentrations of 4 fluoroquinolones: methicillin-susceptible and -resistant Staphylococcus aureus. Int. J. Antimicrob. Agents 24:161-167.[CrossRef][Medline]
  8. Randall, L., S. Cooles, L. Piddock, and M. Woodward. 2004. Mutant prevention concentrations of ciprofloxacin and enrofloxacin for Salmonella enterica. J. Antimicrob. Chemother. 54:688-691.[Abstract/Free Full Text]
  9. Sindelar, G., X. Zhao, A. Liew, Y. Dong, T. Lu, J. Zhou, J. Domagala, and K. Drlica. 2000. Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria. Antimicrob. Agents Chemother. 44:3337-3343.[Abstract/Free Full Text]
  10. 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.[CrossRef][Medline]
  11. Zhao, X., W. Eisner, N. Perl-Rosenthal, B. Kreiswirth, and K. Drlica. 2003. Mutant prevention concentration of garenoxacin (BMS-284756) for ciprofloxacin-susceptible or -resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 47:1023-1027.[Abstract/Free Full Text]
Karl Drlica*
Xilin Zhao
Public Health Research Institute
225 Warren St.
Newark, New Jersey 07103

Joseph M. Blondeau
Christine Hesje
Department of Microbiology and Immunology
University of Saskatchewan
Saskatoon, Saskatchewan
Canada,1

* Phone: (973) 854-3360Fax: (973) 854-3101E-mail: drlica{at}phri.org

Antimicrobial Agents and Chemotherapy, January 2006, p. 403-404, Vol. 50, No. 1
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.1.403-404.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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