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Abstract & commentary
Synopsis: The mutant prevention concentration may be a useful predictor of the relative potential of antibiotics to select resistant mutants.
Source: Blondeau JM, et al. Antimicrob Agents Chemother. 2001;45:433-438.
Blondeau and colleagues determined the mutant prevention concentration (MPC) of 4 fluoroquinolones and 1 naphthyridone against clinical isolates of Streptococcus pneumoniae. Serial concentrations of antibiotic in agar were seeded with 1010 or more of CFU. The MPC was recorded as the lowest antibiotic concentration that allowed no growth after incubation for 24 hours. After omitting data from 6 isolates deliberately included because of their fluoroquinolone resistance, the MIC90 and MPC90 (the concentration below which 90% of isolates had no growth with an inoculum of 1010 CFU) were determined. The MIC90 was 0.25 mg/mL for moxifloxacin and trovafloxacin, 0.5 mg/mL for gatifloxacin and grepafloxacin, and 1.0 mg/mL for levofloxacin. The MPC90 for these same strains was 2.0 mg/mL for moxifloxacin, 4.0 mg/mL for trovafloxacin and gatifloxacin, and 8.0 mg/mL for grepafloxacin and levofloxacin. The ratios of MPC90 to MIC90 was 8 to 16.
Thus, based on their potential for restricting the selection of mutants, as reflected in the MPC, the relative potencies of the drugs studied was moxifloxacin > trovafloxacin > gatifloxacin > grepafloxacin > levofloxacin. The MIC90 ranking was moxifloxacin = trovafloxacin > gatifloxacin > grepafloxacin > levofloxacin.
Comment by Stan Deresinski, MD, FACP
After the recommended 400-mg dose of moxifloxacin the mean peak antibiotic concentration reached is approximately 4.5 mg/mL; the peak after a 400-mg dose of gatifloxacin is slightly lower. The mean peak serum concentration achieved after the recommended 500-mg dose of levofloxacin is approximately 5.7 mg/mL. Both moxifloxacin and gatifloxacin maintain serum concentrations above the S pneumoniae MIC90 for all or most of the 24-hour dosing interval, while levofloxacin may not. In addition, moxifloxacin maintains serum concentrations above the MPC90 for all or most of the dosing interval, while levofloxacin does not. Gatifloxacin has an intermediate level of activity.
An argument has been made that the use of less-active fluoroquinolones for treatment of respiratory tract infection may accelerate the inevitable march of resistance in S pneumoniae to these agents. While only a single parC topoisomerase mutation is necessary for the development of levofloxacin resistance, 2 mutations (parC and gyrA) are necessary for the development of clinically significant resistance to the newer fluoroquinolones. The de novo selection of double mutants from populations of wild-type bacteria occurs at an extremely low frequency—approximately 1014—while a single-step mutation occurs at frequencies as high as 107. Thus, the widespread use of levofloxacin may lead to a large dispersed population of S pneumoniae that may require only a further single mutation to achieve resistance to moxifloxacin or gatifloxacin.
A pharmacodynamic argument reaching the same conclusion has also been made. It has been reported that, for fluoroquinolones, an AUIC (the ratio of the 24-hour area under the curve to the MIC) greater than 100-120 is associated with both improved outcome and reduced risk of selection of resistant mutants. During treatment of pneumococcal infection with a fluoroquinolone, the AUIC is most reliably above this threshold when the newer agents are used.
However, it must be recognized that the human data supporting these conclusions remain scanty. Furthermore, while the concept of the MPC is an attractive one, its validity and relevance remain to be determined. It is possible that it is too simplistic. These studies do not, for instance, take into account antibiotic protein binding, antibiotic tissue kinetics, or host response.
1. Schentag JJ. J Chemother. 1999;11:426-439.
2. Turnidge J. Drugs. 1999;58(Suppl 2):29-36.