MRSA, Fluoroquinolones, and Mutations
Abstract & Commentary
Synopsis: Genetic mutations associated with resistance to fluoroquinolones were frequently detected in MRSA.
Source: Sierra JM, et al. Correlation between the activity of different fluoroquinolones and the presence of mechanisms of quinolone resistance in epidemiologically related and unrelated strains of methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect. 2002;8:781-790.
The microbiology group from Hospital Clinic in Barcelona studied 22 clinical isolates of methicillin-susceptible Staphylococcus aureus and methicillin-resistant S aureus (MRSA). The strains were collected in 1994-1995 in order to determine the inhibitory activity of 5 fluoroquinolones (FQ): ciprofloxacin, norfloxacin, sparfloxacin, levofloxacin, and trovafloxacin, each tested in the presence and absence of reserpine. Reserpine blocks a specific efflux pump, and decreases in the MIC in the presence of reserpine imply the action of such a pump.
The sequence of the gyrase gene and the topoisomerase genes were determined for each strain. Molecular typing was done by cutting the chromosomes of each strain with the restriction enzyme SmaI and separating the fragments by pulse field gel electrophoresis (PFGE).
The results showed that the MRSA were related and that 2 clones predominated. For the MSSA strains, there was much less homology and 7 individual clones were identified. FQ were highly active against the MSSA but much less active against MRSA. Among the MSSA, trovafloxacin had the best activity, with MICs ranging from 0.016 to 1 ug/mL. In fact, 6 of the MSSA strains were susceptible to all the FQ. For the MRSA, MICs ranged from 0.5 to 32 ug/mL. There were only a few strains whose MIC decreased in the presence of reserpine.
FQ resistance mutations were frequent among the MRSA but not among the MSSA. Only 2 MSSA isolates had mutations. These were at the grlA gene at the Ser80 in 2 isolates, while 1 isolate had an additional mutation in the gryA locus. Four MRSA strains had 3 mutations that were the likely cause of increased MICs, including ciprofloxacin up to 128 ug/mL and trovafloxacin up to 32 ug/mL. Mutations in the grlB and gryB genes were infrequent and not associated with increases in MICs.
Comment by Joseph F. John, Jr, MD
More studies like this one are appearing, but this study capsulizes the importance of mutational resistance for the FQ. Certain mutations in the gyrA and grlA genes are associated with resistance and, in general, the greater number of mutations the higher the MICs. These mutations tend to occur against the backdrop of multiresistance, in the case of staphylococci MRSA.
Older FQ showed less activity in this study (norfloxacin, ciprofloxacin, and sparfloxacin) compared to newer FQ (levofloxacin and trovafloxacin). One reason may be that the newer FQ are less susceptible to efflux pumps. MICs for trovafloxacin and levofloxacin were seldom changed by the addition of reserpine. Sparfloxacin susceptibility, on the other hand, is altered primarily by mutations in DNA gyrase since mutations in grlA did not change the sparfloxacin MICs.
One interesting finding of this study was that epidemiologically related strains that were otherwise highly related acquired different mutational-based resistance. One demonstrated reduced MICs to ciprofloxacin and norfloaxcin in the presence of reserpine. Which of these resistance mechanisms emerged first requires further study.
Even though there is little use of trovafloxacin in the United States, it is still valuable to monitor this most active of the FQs because resistance to trovafloxacin serves as a sentinel for the volume of FQ use. Such use may now apparently be at epidemic proportions based on the number of patients who receive agents like levofloxacin in emergency room departments.
As physicians become more and more dependent on FQ as front-line agents for a wide variety of infections, it is important to remember that FQ resistance is more likely to occur in pathogens already showing multiresistance and some studies suggest that increased FQ use constitutes a risk factor for acquisition of nosocomial MRSA.
The isolates used in this study were from 1994-1995 so it is likely that resistance in FQ due to both acquired mutations and to activation of efflux pumps has evolved further. Physicians should stay tuned to these developments since it is crucial to preserve the current level of FQ antimicrobial activity. There are several promising FQs on the horizon, but their activity may be affected by the type of evolving mutational resistance reported in this study. Close vigilance through monitoring of FQ susceptibility, as in this study, will help to guide clinicians in their use of FQ agents.
Dr. John is Co-Editor of Infectious Disease Alert, Chief of Medical Subspecialty Services at Ralph H. Johnson Veterans Administration Medical Center, and Professor of Medicine at the Medical University of South Carolina, Charleston, SC.
Genetic mutations associated with resistance to fluoroquinolones were frequently detected in MRSA.
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