Activities of Mutant Prevention Concentration-Targeted Moxifloxacin and Levofloxacin against
            <i>Streptococcus pneumoniae</i>
            in an In Vitro Pharmacodynamic Model

Allen, George P.; Kaatz, Glenn W.; Rybak, Michael J.

doi:10.1128/aac.47.8.2606-2614.2003

Cited by 54 publications

(49 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results further suggest that GyrA was the most crucial target for development of high-level resistance reflected in high MIC and MPC values for these three fluoroquinolones and the only target sensitive to prolonged antibiotic pressure in MPC experiments. These results are in agreement with previous findings (1,4,18,23,25,27). No clear relationship was found between the MPCs or their ratios to the MICs and the existence of gyrB, parC, or parE mutations.…”

Section: Resultssupporting

confidence: 83%

Comparative Study of the Mutant Prevention Concentrations of Moxifloxacin, Levofloxacin, and Gemifloxacin against Pneumococci

Credito

Kosowska-Shick

McGhee

et al. 2010

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We tested the propensity of three quinolones to select for resistant Streptococcus pneumoniae mutants by determining the mutant prevention concentration (MPC) against 100 clinical strains, some of which harbored mutations in type II topoisomerases. Compared with levofloxacin and gemifloxacin, moxifloxacin had the lowest number of strains with MPCs above the susceptibility breakpoint (P < 0.001), thus representing a lower selective pressure for proliferation of resistant mutants. Only moxifloxacin gave a 50% MPC (MPC 50 ) value (1 g/ml) within the susceptible range.The only three quinolones currently approved to treat community-acquired respiratory tract infections in adults are levofloxacin (500 and 750 mg), moxifloxacin (400 mg), and gemifloxacin (320 mg). When free area under the curve (AUC)/MIC data are compared, moxifloxacin and gemifloxacin yield similar values and are superior to levofloxacin (15,16). These pharmacokinetic/pharmacodynamic considerations relate to efficacy against the susceptible portion of the bacterial population (9, 10). Another criterion, the mutant prevention concentration (MPC), may also impact clinical efficacy by relating to the resistant mutant subpopulations. The MPC, which is the MIC of the least susceptible resistant mutant subpopulation, represents a threshold above which the selective proliferation of the resistant mutant subpopulation is expected to rarely occur. Using this method, Blondeau and colleagues (4) proposed that moxifloxacin and gatifloxacin (a drug no longer available) are more active than levofloxacin in the treatment of pneumococcal pneumonia. Since the least susceptible mutant is usually a drug target mutant, MPC values can be regarded as a measure of the interaction of the quinolone with the mutant target enzyme. However, clinical isolates may contain additional efflux mechanism and/or permeability alterations that potentially may raise the MPC. Thus, measurement of MPC with clinical isolates and integrating that information with pharmacokinetics is important for comparing compounds.In the current study, the MIC and MPC values for 100 recent clinical pneumococcal isolates, each with different ␤-lactam, quinolone, and macrolide phenotypes, were determined for levofloxacin, moxifloxacin, and gemifloxacin. All quinolonenonsusceptible (intermediate as well as resistant) strains, as well as 13 randomly selected quinolone-susceptible strains were tested for the presence of mutations in the quinolone resistance-determining regions (QRDRs) of the gyrA, gyrB, parC, and/or parE genes. MATERIALS AND METHODSMIC and MPC determination. The initial determinations of the MICs for all strains were made using standard agar dilution methodology (5). MICs were also tested during MPC determinations that were performed as follows. Starter cultures were generated by inoculating 12 blood Trypticase soy agar (TSA) plates (BD Diagnostics, Sparks, MD) with pure cultures of each test isolate and incubated overnight at 35°C in air. The cells were then transferred from plates and suspended...

show abstract

Section: Resultssupporting

confidence: 83%

Comparative Study of the Mutant Prevention Concentrations of Moxifloxacin, Levofloxacin, and Gemifloxacin against Pneumococci

Credito

Kosowska-Shick

McGhee

et al. 2010

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Reports by Croisier et al and Allen et al showed that after levofloxacin or moxifloxacin treatment, mutants occur in vivo if there is a preexisting parC mutation since the drug concentrations fall below the MPCs of the strains. Increasing both the drug concentration and exposure to exceed the MPC may prevent mutant strains from emerging, although this strategy did not prevent the selection of secondary mutants in strains with preexisting mutations (2,5).…”

mentioning

confidence: 99%

Fatal Levofloxacin Failure in Treatment of a Bacteremic Patient Infected with Streptococcus pneumoniae with a Preexisting parC Mutation

et al. 2008

View full text Add to dashboard Cite

show abstract

“…However, these in vitro data should be validated in vivo by clinical trials, including full bacteriological documentation and a statistically significant number of cases due to these particular strains. Alternatively, in vitro pharmacokinetic-pharmacodynamic (PK-PD) models might help to predict gatifloxacin efficiency in these specific instances (1,5,15).…”

mentioning

confidence: 99%

Activity of Gatifloxacin in an In Vitro Pharmacokinetic-Pharmacodynamic Model against Staphylococcus aureus Strains either Susceptible to Ciprofloxacin or Exhibiting Various Levels and Mechanisms of Ciprofloxacin Resistance

Ba¹,

Arpin²,

Vidaillac³

et al. 2006

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Gatifloxacin (GAT) is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. Its activity was studied in an in vitro pharmacokinetic-pharmacodynamic model against five Staphylococcus aureus strains, either susceptible to ciprofloxacin or exhibiting various levels and mechanisms of ciprofloxacin (CIP) resistance: the ATCC 25923 reference strain (MICs of CIP and GAT: 0.5 and 0.1 g/ml, respectively), its efflux mutant SA-1 (16 and 0.5 g/ml; mutation in the norA promoter region), and three clinical strains, Sa2102 (2 and 0.2 g/ml), Sa2667 (4 and 0.5 g/ml), and Sa2669 (16 and 1 g/ml), carrying mutations in the grlA (Ser80Tyr or Phe) and gyrA (Ser84Ala) quinolone resistance-determining regions (QRDRs) for Sa2669. Plasmatic pharmacokinetic profiles after daily 1-h perfusion of 400 mg for 48 h were accurately simulated. Thus, mean maximum concentration of drug in serum values for the two administration intervals were 5.36 and 5.80 g/ml, respectively, and the corresponding half-life at ␤-phase values were 8.68 and 7.80 h (goodness of fit coefficient, >0.98). Therapeutic concentrations of GAT allowed the complete eradication of the susceptible strain within 12 h (difference between the bacterial counts at the beginning of the treatment and at a defined time: ؊2.18 at the 1-h time point [t 1 ] and ؊6.80 at t 24 and t 48 ; the bacterial killing and regrowth curve from 0 to 48 h was 30.2 h ؋ log CFU/milliliter). However, mutants (M) with GAT MICs increased by 4-to 40-fold were selected from the other strains. They acquired mutations either supplementary (MSa2102 and MSa2667) or different (Ala84Val for MSa2669) in gyrA or in both gyrA and grlA QRDRs (MSA-1). MSa2667 additionally overproduced efflux system(s) without norA promoter modification. Thus, GAT properties should allow the total elimination of ciprofloxacin-susceptible S. aureus, but resistant mutants might emerge from strains showing reduced susceptibility to older fluoroquinolones independently of the first-step mutation(s).

show abstract

Activities of Mutant Prevention Concentration-Targeted Moxifloxacin and Levofloxacin against Streptococcus pneumoniae in an In Vitro Pharmacodynamic Model

Cited by 54 publications

References 42 publications

Comparative Study of the Mutant Prevention Concentrations of Moxifloxacin, Levofloxacin, and Gemifloxacin against Pneumococci

Comparative Study of the Mutant Prevention Concentrations of Moxifloxacin, Levofloxacin, and Gemifloxacin against Pneumococci

Fatal Levofloxacin Failure in Treatment of a Bacteremic Patient Infected with Streptococcus pneumoniae with a Preexisting parC Mutation

Activity of Gatifloxacin in an In Vitro Pharmacokinetic-Pharmacodynamic Model against Staphylococcus aureus Strains either Susceptible to Ciprofloxacin or Exhibiting Various Levels and Mechanisms of Ciprofloxacin Resistance

Contact Info

Product

Resources

About