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

Abstract

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...

Mutant Selection Window in Levofloxacin and Moxifloxacin Treatments of Experimental Pneumococcal Pneumonia in a Rabbit Model of Human Therapy

“…For strains with a low SI, no mutants were recovered in treated rabbits, either because these strains were Although the MSW is less well delineated for LVX (perhaps due to the limited activity of this antibiotic), our results confirm the concept of the MSW since the PK-PD MPC , PK-PD SI , and PK-PD MSW parameters are associated with the occurrence of mutants in animals infected with parC strains, whereas the PK-PD MIC parameters are not (Table 7). Indeed, the MSW defined by using the MICs is very large and begins at AUC/ MIC ratios that are much higher than the 30 to 50 values usually considered as predictive for the efficacy of fluoroquinolones against pneumococcal infections (3,13,22,40,74 (45). For example, in our model, resistant mutants were recovered for AUC/MICs from 50 to 164.5 with MFX.…”

“…However, further information concerning the in vivo efficacy of new fluoroquinolones is needed. Especially, the risk of in vivo mutations has to be investigated, taking into account the high in vitro rate of mutation of pneumococci when exposed to quinolones (1,6,41,42,45,46,55,66,68,74) compared to beta-lactam agents.…”

Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1

“…Use of progressively larger exposures will begin to affect the resistant subpopulation, causing a decline to their starting value or below. The overall shape of this relationship has been referred to as an "inverted U" (7,8) and is nonmonotonic (Fig. 1).…”

“…The first demonstration of resistance suppression in vivo or in vitro was performed in a murine thigh infection model (11) and an in vitro pharmacodynamic model (8). Pseudomonas aeruginosa was the challenge strain and levofloxacin the drug employed in the animal model (11) and moxifloxacin the drug employed in the in vitro model (8).…”

Fluoroquinolone AUIC Break Points and the Link to Bacterial Killing Rates: In Vitro Models

“…This has been well described previously 3,4 and confirmed by MacGowan et al 5 As well, we need to realize that the immune system in an immunocompetent host may directly or indirectly lower the AUC 24 /MIC ratios required for bacterial eradication, potentially to varied degrees, depending on the organism.…”