<i>Streptococcus pneumoniae</i>
            Response to Repeated Moxifloxacin or Levofloxacin Exposure in a Rabbit Tissue Cage Model

Xuan, Dawei; Zhong, Mingkang; Mattoes, Holly M.; Bui, Khanh Q.; McNabb, JoCarol; Nicolau, David P.; Quintiliani, Richard; Nightingale, Charles H.

doi:10.1128/aac.45.3.794-799.2001

Cited by 25 publications

(25 citation statements)

References 13 publications

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“…Similar observations for levofloxacin were made previously with in vitro and animal pharmacokinetic models using different techniques (13,14 , and we observed a similar phenomenon with moxifloxacin in this in vitro model. It was previously suggested that the emergence of resistance is more likely in strains with efflux pumps than in those without efflux pumps, and some data from in vitro pharmacokinetic models support this notion (Madaras-Kelly et al, 40th ICAAC).…”

Section: Discussionsupporting

confidence: 92%

Mechanism of Fluoroquinolone Resistance Is an Important Factor in Determining the Antimicrobial Effect of Gemifloxacin against Streptococcus pneumoniae in an In Vitro Pharmacokinetic Model

MacGowan

Bowker

2003

Antimicrob Agents Chemother

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Antibacterial effect and emergence of resistance to gemifloxacin and levofloxacin were studied in an in vitro pharmacokinetic model of infection. A panel of Streptococcus pneumoniae strains with known mechanisms of resistance were used; two strains had no known resistance mechanism, two had efflux pumps, three had gyrA plus parC mutations, and one had only a parC mutation. Gemifloxacin MICs were in the range of 0.016 to 0.25 mg/liter, and levofloxacin MICs ranged from 1 to 16 mg/liter. Antimicrobial effect was measured by area under the bacterial-kill curve up to 72 h, and emergence of resistance was determined by population analysis profile before and during drug exposure. The area under the curve (AUC)/MIC ratios for gemifloxacin and levofloxacin were 35 to 544 and 3 to 48, respectively. As expected on the basis of these AUC/MIC ratio differences, antibacterial effect was much greater for gemifloxacin than levofloxacin. In the gemifloxacin simulations, mechanism of resistance as well as MIC determined the antibacterial effect, as indicated by gemifloxacin's greater effect against efflux strains compared to those with gyrA or parC mutations despite similar MICs. This was not true of levofloxacin. Emergence of resistance was not easily demonstrated with either agent, and mechanism of resistance did not have any impact on it.Fluoroquinolone resistance in Streptococcus pneumoniae is, at present, an uncommon occurrence (British Society for Antimicrobial Chemotherapy Working Party, Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., 2001). However, it is well described in terms of its genetic basis and phenotypic expression, being related to either mutations in the quinolone resistance-determining regions (QRDR) of the genome or the presence of efflux pumps in the bacterial membrane. Highlevel fluoroquinolone resistance (ciprofloxacin MIC of 64 mg/ liter) in S. pneumoniae is commonly associated, as determined by DNA sequence analysis, with mutations in parC and gyrA, although changes in parE and gyrB also occur. However, such strains are more susceptible to advanced-generation fluoro- When S. pneumoniae was used in an in vitro model, the presence of efflux pumps reduced the antibacterial effects of levofloxacin, moxifloxacin, and sparfloxacin and promoted the emergence of resistance (K. J. Madaras-Kelly, C. Daniels, M. Hegbloom, C. Nielson, and T. Kurtz, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 296, 2000). In contrast, in a neutropenic murine thigh infection model with S. pneumoniae resistant to ciprofloxacin as a result of efflux or gyrase parC and parE mutations, the gemifloxacin area-underthe-curve (AUC)/MIC ratio needed to produce a net bacteriostatic effect was lower for the efflux pump-containing strains than for the other strains tested (D. Andes and W. A. Craig, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 2032Chemother., abstr. , 1999.To further define the impact of the mechanism of fluoroquinolone resistance on the pharmacodynamic effects of this dru...

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Section: Discussionsupporting

confidence: 92%

Mechanism of Fluoroquinolone Resistance Is an Important Factor in Determining the Antimicrobial Effect of Gemifloxacin against Streptococcus pneumoniae in an In Vitro Pharmacokinetic Model

MacGowan

Bowker

2003

Antimicrob Agents Chemother

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“…Furthermore, detection of the emergence of resistance by comparison of pre-and postexposure MICs may not be as sensitive for detecting changes in resistance as PAPs. Animal data obtained in a rabbit tissue cage model with S. pneumoniae and moxifloxacin exposure for 7 days failed to show any emergence of resistance (17). The exception to these observations in both in vitro and animal models appears to be ciprofloxacin; data indicating resistance detected by changes in MICs or PAPs are easily generated by ciprofloxacin exposure (4,16,18).…”

Section: Discussionmentioning

confidence: 84%

Activities of Moxifloxacin against, and Emergence of Resistance in, Streptococcus pneumoniae and Pseudomonas aeruginosa in an In Vitro Pharmacokinetic Model

MacGowan

Rogers

Holt

et al. 2003

Antimicrob Agents Chemother

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The pharmacodynamics of moxifloxacin against Streptococcus pneumoniae and Pseudomonas aeruginosa were investigated in a pharmacokinetic infection model. Three strains of S. pneumoniae, moxifloxacin, and two strains of P. aeruginosa were used. Antibacterial effect and emergence of resistance were measured for both species over a 72-h period using an initial inoculum of about 10 8 CFU/ml. At equivalent area under the curve (AUC)/MIC ratios, S. pneumoniae was cleared from the model while P. aeruginosa was not. For S. pneumoniae, the area under the bacterial kill curve up to 72 h could be related to AUC/MIC ratio using an inhibitory maximum effect (E max ) model (concentration required for 50% E max [EC 50 ], 45 ؎ 22; r 2 , 0.97). For P. aeruginosa even at the highest AUC/MIC ratio (427), bacterial clearance was insufficient for the EC 50 to be calculated. Emergence of resistance occurred with P. aeruginosa but not to any significant extent with S. pneumoniae. Emergence of resistance in P. aeruginosa as measured by population analysis profile (PAP-AUC) was dependent on drug exposure and time of exposure. In weighted least-squares regression analysis AUC/MIC ratio was predictive of PAP-AUC. When emergence of resistance was measured by the time for the colony counts on media containing antibiotic to increase by 2 logs, again AUC/MIC was the best predictor of emergence of resistance. However, for both experiments using S. pneumoniae and P. aeruginosa the correlation between all the pharmacodynamic parameters was high. These data indicate that for a given fluoroquinolone the magnitude of the AUC/MIC ratio for antibacterial effect is dependent on the bacterial species. Emergence of resistance is dependent on (i) species, (ii) duration of drug exposure, and (iii) drug exposure. A single AUC/MIC ratio magnitude is not adequate to predict antibacterial effect or emergence of resistance for all bacterial species.In vitro pharmacokinetic models of infection are widely used to study antibacterial pharmacodynamics, especially within the fluoroquinolone drug class. It is known that area under the curve (AUC)/MIC is the main pharmacokinetic/pharmacodynamic index related to the antibacterial effects of fluoroquinolones in in vitro models. In 1996, Madaras-Kelly et al. (15) studied the pharmacodynamics of ofloxacin and ciprofloxacin against three strains of Pseudomonas aeruginosa. The area under the bacterial killing curve (AUBKC) was used as the measure of antibacterial effects. Multivariate regression analysis indicated that the AUC/MIC was related to the antibacterial effect and that this relationship was well described by a sigmoid maximum-effect (E max ) model, the AUC/MIC at which 50% of the isolates were inhibited (MIC 50 ) being about 120 and the maximum antibacterial effect occurring at an AUC/MIC of 400 to 600. With similar techniques, the effects of levofloxacin, ofloxacin, and ciprofloxacin on Streptococcus pneumoniae were tested. Again, with an E max model to relate the AUC/MIC and the antibacterial effect, the AUC/MIC...

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“…Urine concentrations were measured at these collection times by a validated high-performance liquid chromatographic method [6]. The mean (±S.D.)…”

Section: Urine Samplesmentioning

confidence: 99%

Urinary concentrations and bactericidal activities of newer fluoroquinolones in healthy volunteers

Stein

Schooley

2004

International Journal of Antimicrobial Agents

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Streptococcus pneumoniae Response to Repeated Moxifloxacin or Levofloxacin Exposure in a Rabbit Tissue Cage Model

Cited by 25 publications

References 13 publications

Mechanism of Fluoroquinolone Resistance Is an Important Factor in Determining the Antimicrobial Effect of Gemifloxacin against Streptococcus pneumoniae in an In Vitro Pharmacokinetic Model

Mechanism of Fluoroquinolone Resistance Is an Important Factor in Determining the Antimicrobial Effect of Gemifloxacin against Streptococcus pneumoniae in an In Vitro Pharmacokinetic Model

Activities of Moxifloxacin against, and Emergence of Resistance in, Streptococcus pneumoniae and Pseudomonas aeruginosa in an In Vitro Pharmacokinetic Model

Urinary concentrations and bactericidal activities of newer fluoroquinolones in healthy volunteers

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