Overstretching the mutant prevention concentration

David M. Livermore*

Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency, 61 Colindale Avenue, London NW9 5HT, UK

Keywords: resistance, selection pressure, mutation

Sir,

Smith et al.1 make the good point that mutant prevention concentrations (MPCs, i.e. those drug levels that inhibit first-step mutants, militating against their clinical selection) are relevant only for antibiotic/organism combinations where resistance is mostly mutational, not for those where it usually involves species selection or DNA transfer. These authors do, however, underplay the role of mutational resistance, suggesting it is essentially restricted to fluoroquinolones. In reality, most resistance to ß-lactams and aminoglycosides in Pseudomonas aeruginosa is contingent on mutations,2 as is most cephalosporin resistance in the Enterobacter, Citrobacter, Serratia group. Likewise, the initial emergence—though not the later spread— of TEM and SHV extended-spectrum ß-lactamases entails mutation. In all these cases, the MPC has some potential relevance.

Perhaps a greater limitation than occasional misapplication is that the MPC’s proponents mostly consider only the target pathogen, and not other skin or gut organisms that are collaterally exposed, and which may be future opportunist pathogens. Whilst (say) the concentrations of a new fluoroquinolone in respiratory secretions may exceed the MPC for pneumococci, this condition may not be met for skin staphylococci, exposed via the sweat, nor for gut Enterobacteriaceae, which are exposed to any unabsorbed antibiotic and to any that is excreted via the bile.

In short, the MPC should be seen specifically as a measure of the risk of mutational resistance being selected, during therapy, in the primary pathogen, not (as sometimes implied) as a general proxy for the ecological consequences of an antibiotic’s use.

Footnotes

* Tel: +44-20-8200-444; Fax: +44-20-8358-3292; E-mail: david.livermore{at}hpa.org.uk Back

References

1 . Smith, H. J., Nichol, K. A., Hoban, D. J. et al. (2003). Stretching the mutant prevention concentration (MPC) beyond its limits. Journal of Antimicrobial Chemotherapy 51, 1323–5.[Free Full Text]

2 . Livermore, D. M. (2002). Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clinical Infectious Diseases 34, 634–40.[CrossRef][ISI][Medline]





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