Stretching the mutant prevention concentration (MPC) beyond its limits

Antibiotic resistance is increasingly recognized as a serious global problem. The mutant prevention concentration (MPC) is a novel concept1 that has been employed in the evaluation of an antibiotic’s ability to minimize or limit the development of resistant organisms.2 The MPC has been defined as the MIC of the least susceptible single-step mutant.1,2 By definition, cell growth in the presence of antibiotic concentrations greater than the MPC requires an organism to have developed two or more resistance-causing spontaneous chromosomal point mutations.1,2 The MPC concept may have potential use in the evaluation of various fluoroquinolones’ abilities to limit the selection of resistant mutants, because resistance mutations observed in the clinical setting are the same mutations observed in the laboratory setting when performing MPC studies (i.e. development of spontaneous chromosomal point mutations). The majority of data published on the fluoroquinolones has been regarding their activity against Streptococcus pneumoniae, Staphylococcus aureus and Mycobacterium spp.1,2 Recently, MPC research has been carried out with other classes of agents, such as the β-lactam antibiotics, macrolides and aminoglycosides.3–7 However, the primary resistance mechanisms for these antibiotics are not the development of spontaneous chromosomal point mutations (Table 1), but the acquisition of foreign DNA. It is essential that the mechanisms of resistance development, both biochemical and genetic, be considered prior to the application of the MPC to classes of antibiotics other than the fluoroquinolones. Recently, MPCs have been reported for β-lactam antibiotics in studies conducted with Acinetobacter baumannii, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, S. aureus and Stenotrophomonas maltophilia.3,4,6 As β-lactam resistance is primarily attributed to the presence of β-lactamases, the MPCs that are obtained do not accurately reflect the in vivo resistance mechanisms (Table 1). MPC studies of aminoglycosides have been conducted with organisms including A. baumannii, C. freundii, E. cloacae, E. coli, K. pneumoniae, P. aeruginosa, S. aureus and S. maltophilia.3,4,6 Aminoglycoside resistance is primarily attributed to the presence of inactivating enzymes that are acquired.9,10 Thus, the MPCs that are obtained during studies with aminoglycosides do not accurately reflect in vivo resistance mechanisms (Table 1). As with the β-lactam antibiotics, MPC studies with aminoglycosides evaluate mechanisms of resistance that are not truly indicative of the primary resistance mechanism which occurs in the clinical setting. Akins et al.3,4 reported this occurrence, as they were able to establish a correlation between MICs and MPCs for the fluoroquinolones but not for the β-lactam antibiotics or aminoglycosides. These authors concluded that MPCs are not predictive of the activity of aminoglycosides and β-lactam antibiotics.3,4 In addition, MPCs have been determined for macrolides with S. pneumoniae.7 The results of MPC studies with macrolides report that a variety of mutations developed in the erm(B) and mef(A)/(E) genes.7 The resulting MPCs are based on the development of mutations within the resistance genes; however, it is the acquisition of the erm(B) or mef(A)/(E) genes themselves from other organisms that results in clinically observed resistance. Thus, MPC studies of macrolides do not evaluate the resistance mechanisms observed in clinical isolates. As antimicrobial resistance increases worldwide, there is a great need to develop methods to limit its further spread. The MPC is a concept that has been developed in the hope of altering dosing regimes such that the growth of resistant organisms could be curtailed. The application of this novel concept during antibiotic therapy may have the potential to limit resistance development for antibiotic–organism pairings in which the in vivo mechanisms of resistance correspond with those evaluated in in vitro MPC studies, i.e. spontaneous point mutations. However, caution must prevail in the utility of MPC studies conducted on antibiotic–organism pairings in which other mechanisms, such as the presence of inactivating enzymes and efflux, are the primary cause of resistance. Knowledge of both the biochemical (efflux, decreased cellular uptake, β-lactamases) and genetic (spontaneous chromosomal point mutations or uptake of exogenous DNA) mechanisms of resistance primarily attributing to a particular organism’s development of resistance is required prior to determining MPCs. The ideal situation for evaluating an MPC requires an organism–antibiotic pairing to have the development of spontaneous chromosomal point mutations as its primary resistance mechanism. This is currently only the case with the fluoroquinolones. Conversely, an MPC study conducted with β-lactam antibiotics and an organism the primary resistance mechanism of which is the acquisition of β-lactamases is not able to evaluate the organism’s ability to acquire a β-lactamase and become resistant. Thus, a study such as this or one conducted with aminoglycosides or macrolides would not be indicative of a particular agent’s ability to limit the development of resistant organisms. The MPC concept can only be applied to situations in which the evaluated resistance mechanisms are the same as those observed in the clinical setting. Only then may the MPC be a tool by which the development of resistant organisms can be limited. Correspondence address. Clinical Microbiology, Health Sciences Centre, MS673–820 Sherbrook Street, Winnipeg, Manitoba, Canada R3A 1R9. Tel: +1-204-787-4684; Fax: +1-204-787-4699; E-mail: smithhj14@hotmail.com Applicability of MPC studies for various antibiotic classes based on their primary mechanisms of resistance aNot applicable if due to acquisition of β-lactamase. Not known whether MPC study reflects induction or derepression as observed in clinical isolates. Applicability of MPC studies for various antibiotic classes based on their primary mechanisms of resistance aNot applicable if due to acquisition of β-lactamase. Not known whether MPC study reflects induction or derepression as observed in clinical isolates. 1Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Manitoba; Departments of 2Clinical Microbiology and 3Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada

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