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JAC Advance Access originally published online on April 27, 2006
Journal of Antimicrobial Chemotherapy 2006 58(1):112-116; doi:10.1093/jac/dkl159
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Pharmacodynamic activity of garenoxacin against ciprofloxacin-resistant Streptococcus pneumoniae

George G. Zhanel1–,3,*, Joanne James1, Sheldon Derkatch1, Nancy Laing1,3, Ayman M. Noreddin4 and Daryl J. Hoban1,2

1 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba 5th floor, Basic Medical Sciences Building, 730 William Avenue, Winnipeg, Canada R3E 0W3 2 Department of Clinical Microbiology, MS673 Health Sciences Centre 820 Sherbrook Street, Winnipeg, Canada R3A 1R9 3 Department of Medicine, MS673 Health Sciences Centre 820 Sherbrook Street, Winnipeg, Canada R3A 1R9 4 College of Pharmacy, University of Minnesota 1208 Kirby Drive, Duluth, MN 55812, USA

*Correspondence address. Department of Microbiology, Health Sciences Centre, MS673, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada. Tel: +1-204-787-4902; Fax: +1-204-787-4699; E-mail: ggzhanel{at}pcs.mb.ca

Received 31 January 2006; returned 13 March 2006; revised 30 March 2006; accepted 3 April 2006


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Background: The pharmacodynamic parameter that best correlates with bacteriological eradication for fluoroquinolones is the free (f) area under the 24 h serum concentration curve (AUC24) to MIC (fAUC24/MIC) ratio. This study assessed garenoxacin fAUC24/MIC against ciprofloxacin-resistant Streptococcus pneumoniae using an in vitro pharmacodynamic model.

Methods: A total of 14 S. pneumoniae including 1 fluoroquinolone-susceptible and 13 ciprofloxacin-resistant S. pneumoniae (ParC, efflux, ParC with efflux, and ParC and GyrA) were studied. The quinolone-resistance determining regions (QRDRs) of parC and gyrA were sequenced and efflux was assessed using a reserpine assay. S. pneumoniae with garenoxacin MICs (mg/L) [number of strains] studied were: 0.03 [1], 0.06 [2], 0.12 [2], 0.25 [2], 0.5 [3], 1 [2] and 2 [2]. The in vitro pharmacodynamic model was inoculated with 1 x 106 cfu/mL and garenoxacin was dosed once daily at 0 and 24 h to simulate fAUC24 and t1/2 obtained after standard oral doses in healthy volunteers (400 mg once daily, free AUC24 20 mg·h/L, t1/2 16 h). Sampling was performed over 48 h to assess viable growth.

Results: Garenoxacin fAUC24/MIC achieved in the model ranged from 12 to 800. Garenoxacin fAUC24/MIC 200–800 was bactericidal (≥3 log10 killing) at 6, 24 and 48 h against ciprofloxacin-resistant S. pneumoniae mutants including ParC mutants only, efflux mutants only and ParC/efflux mutants. Garenoxacin fAUC24/MIC 48–96 was bactericidal (≥3 log10 killing) at 24 and 48 h against all ciprofloxacin-resistant S. pneumoniae mutants. Garenoxacin fAUC24/MIC ≤ 24 (against ParC and GyrA mutants) resulted in a bacteriostatic effect with regrowth at 24 and 48 h.

Conclusions: Garenoxacin was bactericidal against ciprofloxacin-resistant S. pneumoniae at fAUC24/MIC ≥ 48. Garenoxacin fAUC24/MIC ≤ 24 resulted in a bacteriostatic effect with regrowth at 24 and 48 h.

Keywords: S. pneumoniae , resistance , fluoroquinolones


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Ciprofloxacin, the first fluoroquinolone to be used for the treatment of community-acquired respiratory infections demonstrates poor potency against Streptococcus pneumoniae, an important pathogen in community-acquired respiratory infections.1,2 New fluoroquinolones such as gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin, with significantly greater activity than ciprofloxacin against S. pneumoniae have recently been developed.1–4 The enhanced pharmacodynamic potency (relative to ciprofloxacin) of these new fluoroquinolones results from their more potent intrinsic activity against S. pneumoniae (manifested by lower MICs), as well as greater free ( f )5 areas under the curve (fAUC24) due to higher bioavailability.6–9 These in turn result in a greater free area under the curve to MIC ratios fAUC24/MIC of the new fluoroquinolones for S. pneumoniae.6–9 We have recently demonstrated that these greater fAUC24/MIC ratios of fluoroquinolones versus S. pneumoniae result in rapid and extensive bactericidal activity in an in vitro pharmacodynamic model with new fluoroquinolones, with no regrowth over the 48 h study period.9 Ciprofloxacin, by comparison, demonstrated only a bacteriostatic effect against multidrug-resistant (ciprofloxacin-susceptible) S. pneumoniae and regrowth occurred during therapy.8

The growing prevalence of penicillin-resistant, macrolide-resistant and recently ciprofloxacin-resistant S. pneumoniae have been reported worldwide.3,4,10,11 Although all the new fluoroquinolones rapidly eradicate penicillin-resistant and macrolide-resistant strains, it is much more difficult for new fluoroquinolones to eradicate ciprofloxacin-resistant (ParC, efflux, ParC with efflux, and ParC and GyrA) [ciprofloxacin MIC; ≥4 mg/L] S. pneumoniae.12 The purpose of this study was to assess the activity of the new fluoroquinolone garenoxacin (currently undergoing Phase III studies) against ciprofloxacin-resistant S. pneumoniae using an in vitro pharmacodynamic model.


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Bacterial strains and culture conditions

One wild-type fluoroquinolone-susceptible and 13 ciprofloxacin-resistant S. pneumoniae obtained from an ongoing CROSS-Canadian Respiratory Organism Susceptibility Study were investigated (Table 1).10 The 13 ciprofloxacin-resistant S. pneumoniae included four different resistance phenotypes including, ParC mutation alone, efflux mutant alone, ParC mutant with efflux, and ParC and GyrA. Strains were of a variety of serotypes and from different regions of Canada.13,14


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  		Table 1. Susceptibility of S. pneumoniae to fluoroquinolones and comparators

 
For the pharmacodynamic studies, logarithmic phase cultures were prepared at a density equivalent to that of a 0.5 McFarland standard (1 x 108 cfu/mL) by suspending several colonies in cation-supplemented Mueller–Hinton broth with 2.5% lysed horse blood. This suspension was diluted 1:100 and 20 µL of the diluted suspension was further diluted in 60 mL of cation-supplemented Mueller–Hinton broth with 2.5% lysed horse blood (Oxoid, Nepean, Ontario). Following overnight growth at 37°C, suspensions were further diluted 1:10 and ~60 mL of the diluted suspension was added to the in vitro pharmacodynamic model. Viable bacterial counts consistently yielded a starting inoculum of ~1 x 106 cfu/mL.9,12

Antibiotic preparations and susceptibility testing

Antibiotic agents were obtained as laboratory-grade powders from their respective manufacturers (ciprofloxacin and moxifloxacin, Bayer, Mississauga, Ontario; garenoxacin and gatifloxacin, Bristol-Myers Squibb, Montreal, Quebec; gemifloxacin, Glaxo-SmithKline, Toronto, Ontario: levofloxacin, Janssen Ortho, Ajax, Ontario), stock solutions were prepared and dilutions were made according to the Clinical Laboratory Standards Institute-CLSI (formerly NCCLS) M7-A6 method.15 Following two subcultures from frozen stock, antimicrobial agent MICs for the isolates were determined by the CLSI-approved broth microdilution method.15 All MICs were performed in triplicate on separate days.

PCR amplification and DNA sequence analysis

Chromosomal DNA from each S. pneumoniae isolate was obtained by established methods and used as a template for PCR. For target gene amplification, the primers as previously described by Morrissey et al. were adapted.13,16 PCR conditions consisted of initial incubation at 94°C for 5 min followed by 30 cycles at 94°C for 45 s, 55°C for 30 s, and 72°C for 2.5 min and a final extension at 72°C for 7 min. Amplified gyrA and parC fragments were analysed by agarose gel electrophoresis and purified with Microcon microconcentrators (Millipore, Bedford, Massachusetts, USA) using the manufacturer's instructions. DNA retrieval was verified by gel electrophoresis and the purified products were quantified using a spectrophotometer. DNA sequencing was carried out using an ABI PRISMTM BigDye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems, Foster City, CA, USA). Primers used for sequencing were adapted as described by Morrissey et al.13,16 Sequencing conditions consisted of 25 cycles at 96°C for 10 s, 50°C for 5 s and 60°C for 4 min. Sequences were obtained using an ABI PRISMTM 310 Genetic Analyzer (Applied Biosystems) and analysed using Sequence Navigator (Applied Biosystems).

Pharmacokinetics of fluoroquinolones in the in vitro pharmacodynamic model

Experiments were performed simulating peak serum concentrations (Cmax) and AUCs of garenoxacin achieved in human serum after standard oral doses (garenoxacin 400 mg once daily) (Table 2).1,17 Protein-free (unbound) serum concentrations were simulated using known protein-binding fractions (garenoxacin 75%).1,17 The simulated garenoxacin serum half-life was 16 h.1,17 The pharmacokinetics of garenoxacin was evaluated by dosing 400 mg once daily in the central compartment and sampling from this compartment at 0, 1, 2, 4, 6, 12, 18, 24, 36 and 48 h. Drug concentrations in each sample were measured by disc diffusion bioassay using a susceptible strain of Bacillus subtilis.9,12 The linear range of the bioassay was 0.1–7 mg/L. The fAUC24 (mg·h/L) for garenoxacin was calculated using the trapezoidal rule.9,12 The fAUC24/MIC was calculated for garenoxacin against the specific S. pneumoniae strain studied.


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  		Table 2. Garenoxacin pharmacodynamic parameters simulated

 
In vitro pharmacodynamic model/pharmacodynamic experiments

The in vitro pharmacodynamic model used in this study has been previously described.9,12 The bacterial inoculum at ~1 x 106 cfu/mL was introduced into the central compartment (volume; 610 mL) of the in vitro pharmacodynamic model and exposed to garenoxacin simulating free (protein unbound) serum concentrations obtained after standard dosing. Growth controls were run in parallel with drug exposure for each experiment. Pharmacodynamic experiments were performed in cation-supplemented Mueller–Hinton broth with 2.5% lysed horse blood in ambient air at 37°C. At 0, 1, 2, 4, 6, 12, 18, 24, 36 and 48 h, samples were removed from the central compartment and viable bacteria counted by plating 100 µL of serial 10-fold dilutions onto cation-supplemented Mueller–Hinton agar with 2.5% lysed horse blood. Plates were incubated overnight at 37°C in ambient air. The lowest limit of detection was 200 cfu/mL (20 µL of an undiluted sample with 20 colonies minimum). Antibiotic carryover was prevented by adding 1% w/v MgCl2 to the Mueller–Hinton agar supplemented with 2.5% lysed horse blood to samples before plating.9,12


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The susceptibility patterns of the 14 S. pneumoniae including 1 fluoroquinolone-susceptible and 13 ciprofloxacin-resistant S. pneumoniae (ParC, efflux, ParC with efflux, and ParC and GyrA) are described in Table 1. Garenoxacin MICs (mg/L) [number of strains] studied were: 0.03 [1], 0.06 [2], 0.12 [2], 0.25 [2], 0.5 [3], 1 [2] and 2 [2]. Four different characterized phenotypes were chosen including a ParC mutant only, efflux only, ParC with efflux, and ParC and GyrA. These mutants represented both low-level (MIC 4–8 mg/L) ciprofloxacin-resistant S. pneumoniae and high-level (MIC ≥ 16 mg/L) ciprofloxacin-resistant S. pneumoniae and also demonstrated typical target site (ParC and GyrA) changes in quinolone-resistance determining regions (QRDRs). The order of fluoroquinolone potency (MIC only) against ciprofloxacin-resistant S. pneumoniae was gemifloxacin > garenoxacin > moxifloxacin > gatifloxacin > levofloxacin > ciprofloxacin (Table 1).

The achieved pharmacokinetic profiles of garenoxacin in the central compartment of the pharmacodynamic model were within 15–20% of simulated (simulated: fCmax 2.0 mg/L, t1/2 16.0 h and fAUC24 20 mg·h/L) pharmacokinetic values. Achieved garenoxacin pharmacokinetics were fCmax 1.80 ± 0.3 mg/L, t1/2 15.2 ± 2.1 h and fAUC24 24.0 mg·h/L. The achieved garenoxacin pharmacodynamics were fCmax/MIC 0.9–60 and fAUC24/MIC 12–800 (Table 2).

Figure 1 shows the pharmacodynamic activity of garenoxacin against selected ciprofloxacin-resistant S. pneumoniae.


Figure 1
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  		Figure 1. Pharmacodynamic activity of garenoxacin against selected ciprofloxacin-resistant S. pneumoniae. Closed diamonds, wild-type growth control; closed triangles, strain 2670; closed circles, strain 18705; open triangles, strain 10277; closed squares, strain 4030; open diamonds, strain 17012; plus symbols, strain 52418; open squares, strain 2118.

 
The pharmacodynamic activity of garenoxacin against ciprofloxacin-resistant S. pneumoniae, simulating free serum concentrations, is displayed in Table 3. Garenoxacin fAUC24/MIC 200–800 was bactericidal (≥3 log10 killing) at 6, 24 and 48 h against ciprofloxacin-resistant S. pneumoniae mutants including ParC mutants only, efflux mutants only and ParC/efflux mutants (Table 3). Garenoxacin fAUC24/MIC 48–96 was bactericidal (≥3 log10 killing) at 24 and 48 h against ciprofloxacin-resistant S. pneumoniae mutants including ParC/efflux mutants and some ParC/GyrA mutants. Garenoxacin fAUC24/MIC ≤ 24 (all ParC and GyrA mutants) resulted in a bacteriostatic effect with regrowth at 24 and 48 h. The observed MICs of garenoxacin for S. pneumoniae studied in the in vitro model did not change during the 48 h period, even for strains where regrowth occurred. Specifically, for strains 14033, 52418, 55374 and 21181 with garenoxacin MICs of 1, 1, 2 and 2 mg/L, respectively and fAUC24/MIC ≤ 24; regrowth occurred at 24 h, yet no increase in garenoxacin MIC was observed on plates inoculated with garenoxacin 2x, 4x and 8x MIC (Table 3).


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  		Table 3. Garenoxacin killing of S. pneumoniae simulating free serum concentrations

 

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As ciprofloxacin-resistant S. pneumoniae is increasing in Canada and other countries, it is important to assess the pharmacodynamic activity of new fluoroquinolones against this phenotype.11,18 Thus we used an in vitro pharmacodynamic model to simulate pharmacokinetic parameters (fCmax and fAUC24) of garenoxacin at standard oral doses used for the treatment of community-acquired respiratory infections such as pneumonia.1,17 These 14 strains chosen for study were selected because they represented both low-level (MIC 4–8 mg/L) ciprofloxacin-resistant S. pneumoniae and high-level (MIC ≥ 16 mg/L) ciprofloxacin-resistant S. pneumoniae and also demonstrated typical target site (ParC and GyrA) changes in QRDRs.13

This study showed that when simulating garenoxacin fAUC24/MIC 200–800, this fluoroquinolone is bactericidal (≥3 log10 killing) at 6, 24 and 48 h against ciprofloxacin-resistant S. pneumoniae mutants including ParC mutants only, efflux mutants only and ParC/efflux mutants (Table 3). Once the garenoxacin fAUC24/MIC is reduced to 48–96, this fluoroquinolone is still bactericidal at 24 and 48 h (not 6 h) against ParC/efflux mutants and selected ParC/GyrA mutants. However, once the garenoxacin fAUC24/MIC is ≤24 (most ParC/GyrA mutants) this fluoroquinolone is bacteriostatic with regrowth at 24 and 48 h. This is consistent with previous reports that showed excellent eradication of S. pneumoniae with respiratory fluoroquinolones achieving an fAUC24/MIC of ≥30.8,9,12,19,20

Garenoxacin has been reported to be active against ciprofloxacin-resistant S. pneumoniae including ParC and GyrA mutants.21,22 In S. aureus, garenoxacin has been documented both genetically and biochemically to be a dual targeting agent of both topoisomerase IV and gyrase.23 Pharmacokinetically, garenoxacin although highly protein-bound (~75%) achieves a high fAUC24 (~20 mg·h/L) resulting in a very high fAUC24/MIC (~800) and rapid bacterial killing of ciprofloxacin-susceptible S. pneumoniae (Table 2).17,24,25 Even against ciprofloxacin-resistant S. pneumoniae with ParC mutations, garenoxacin achieves high fAUC24/MIC (~96–400) resulting in bacterial killing (Tables 2 and 3). Garenoxacin pharmacodynamics in epithelial lining fluid (ELF) would also be expected to be high as the agent achieves high fAUC24 in ELF.26 Using an in vitro pharmacodynamic model, Lister et al.27 reported that a garenoxacin fAUC24/MIC ~30 was required for eradication of S. pneumoniae from the model. Using a neutropenic mouse thigh infection model, Nicolau et al.28 reported that a garenoxacin fAUC24/MIC ~40 versus S. pneumoniae, was required for optimization of bactericidal activity and maximal survival. It has also been reported that garenoxacin has a post-antibiotic effect of 1.4–8.2 h with S. pneumoniae.29 Using a mouse pneumonia model, Azoulay-Dupuis et al.30 reported that garenoxacin was highly effective in eradicating both wild-type fluoroquinolone-susceptible and fluoroquinolone-resistant S. pneumoniae with single mutations (e.g. ParC) but not fluoroquinolone-resistant S. pneumoniae harbouring double mutations (e.g. ParC and GyrA).

In summary, garenoxacin is bactericidal against ciprofloxacin-susceptible and ciprofloxacin-resistant (ParC, efflux or ParC/efflux) S. pneumoniae when achieving fAUC24/MIC ≥ 48; however, garenoxacin is bacteriostatic with regrowth at 24 and 48 h against ciprofloxacin-resistant (ParC/GyrA) S. pneumoniae with fAUC24/MIC ≤ 24.


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G. G. Z. received research funding from fluoroquinolone companies Bayer, Bristol-Myers Squibb, Glaxo-SmithKline and Ortho McNeil; J. J., none; S. D., none; N. L., none; A. M. N., none; D. J. H., received research funding from fluoroquinolone companies Bayer, Bristol-Myers Squibb, Glaxo-SmithKline and Ortho McNeil.


   Acknowledgements
 
This study was supported in part by the University of Manitoba.


   References
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1 Zhanel GG, Ennis K, Vercaigne L, et al. (2002) A critical review of the new fluoroquinolones: focus on respiratory infections. Drugs 62:13–59.[CrossRef][Web of Science][Medline]

2 Bush K and Goldschmidt R. (2000) Effectiveness of fluoroquinolones against gram-positive bacteria. Curr Opin Investig Drugs 1:22–30.[Medline]

3 Doern GV, Pfaller MA, Kugler K, et al. (1998) Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in North American: 1997 results from the SENTRY antimicrobial surveillance program. Clin Infect Dis 27:764–70.[Web of Science][Medline]

4 Sahm DF, Jones ME, Hickey ML, et al. (2000) Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated in Asia and Europe, 1997–1998. J Antimicrob Chemother 45:457–66.[Abstract/Free Full Text]

5 Mouton JW, Dudley MN, Cars O, et al. (2005) Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update. J Antimicrob Chemother 55:601–7.[Abstract/Free Full Text]

6 Wright DH, Brown GH, Peterson ML, et al. (2000) Application of fluoroquinolone pharmacodynamics. J Antimicrob Chemother 46:669–84.[Abstract/Free Full Text]

7 MacGowan A, Rogers C, Bowker KE. (2000) The use of in vitro pharmacodynamic models of infection to optimize fluoroquinolone dosing regimens. J Antimicrob Chemother 46:163–70.[Free Full Text]

8 Lister PD and Sanders CC. (1999) Pharmacodynamics of levofloxacin and ciprofloxacin against Streptococcus pneumoniae. J Antimicrob Chemother 43:79–86.[Medline]

9 Zhanel GG, Karlowsky JA, Walters M, et al. (2001) In vitro pharmacodynamic modelling simulating free serum concentrations of fluoroquinolones against multi-drug resistant Streptococcus pneumoniae. J Antimicrob Chemother 47:435–40.[Abstract/Free Full Text]

10 Zhanel GG, Palatnick L, Nichol L, et al. (2003) Five year incidence of antimicrobial resistance in respiratory tract isolates of Streptococcus pneumoniae: results of a Canadian Respiratory Organism Susceptibility Study (CROSS), 1997–2002. Antimicrob Agents Chemother 43:2504–9.

11 Chen DK, McGeer A, deAzavedo JC, et al. (1999) Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N Engl J Med 341:233–9.[Abstract/Free Full Text]

12 Zhanel GG, Roberts D, Laing N, et al. (2002) Pharmacodynamic activity of fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae. J Antimicrob Chemother 49:807–12.[Abstract/Free Full Text]

13 Zhanel GG, Walkty A, Nichol A, et al. (2003) Molecular characterization of resistant Streptococcus pneumoniae clinical isolates obtained from across Canada. Diagn Microbiol Infect Dis 45:63–7.[CrossRef][Web of Science][Medline]

14 Nichol K, Zhanel GG, Hoban DJ. (2003) Molecular epidemiology of penicillin-resistant and ciprofloxacin-resistant Streptococcus pneumoniae in Canada. Antimicrob Agents Chemother 47:804–8.[Abstract/Free Full Text]

15 National Committee for Clinical Laboratory Standards. (2003) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Sixth Edition: Approved Standard M7-A6 (NCCLS, Wayne, PA, USA).

16 Morrissey I and George J. (1999) Activities of fluoroquinolones against Streptococccus pneumoniae type II topoisomerases purified as recombinant proteins. Antimicrob Agents Chemother 43:2579–85.[Abstract/Free Full Text]

17 Zhanel GG, Fontaine S, Adam S, et al. Respiratory fluoroquinolones: a comparative review. Treat Respir Med (in press).

18 Linares J, de la Campa AG, Pallares R, et al. (1999) Fluoroquinolone resistance in Streptococcus pneumoniae. N Engl J Med 341:1546.[Free Full Text]

19 MacGowan A, Bowker KE, Wootton M, et al. (1999) Activity of moxifloxacin administered once a day against Streptococcus pneumoniae in an in vitro pharmacodynamic model of infection. Antimicrob Agents Chemother 43:1560–4.[Abstract/Free Full Text]

20 Lacy MK, Lu W, Xu X, et al. (1999) Pharmacodynamic comparisons of levofloxacin, ciprofloxacin and ampicillin against Streptococcus pneumoniae in an in vitro model of infection. Antimicrob Agents Chemother 43:672–7.[Abstract/Free Full Text]

21 Christiansen KJ, Bell JM, Turnidge JD, et al. (2001) Antimicrobial activities of garenoxacin (BMS 284756) against Asia-Pacific region clinical isolates from the SENTRY program, 1999–2001. Antimicrob Agents Chemother 48:2049–55.

22 Morosini MI, Loza E, del Campo R, et al. (2003) Fluoroquinolone-resistant Streptococcus pneumoniae in Spain: activities of garenoxacin against clinical isolates including strains with altered topoisomerases. Antimicrob Agents Chemother 48:2692–5.[CrossRef]

23 Ince D, Zhang X, Silver LC, et al. (2002) Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T-3811ME), a new desfluoroquinolone. Antimicrob Agents Chemother 46:3370–80.[Abstract/Free Full Text]

24 Gajjar DA, Bello A, Ge Z, et al. (2003) Multiple-dose safety and pharmacokinetics of oral garenoxacin in healthy subjects. Antimicrob Agents Chemother 47:2256–63.[Abstract/Free Full Text]

25 Van Wart S, Phillips L, Ludwig EA, et al. (2004) Population pharmacokinetics and pharmacodynamics of garenoxacin in patients with community-acquired respiratory tract infections. Antimicrob Agents Chemother 48:4766–77.[Abstract/Free Full Text]

26 Andrews J, Honeybourne D, Jevons G, et al. (2003) Concentrations of garenoxacin in plasma, bronchial mucosa, alveolar macrophages, and epithelial lining fluid following a single oral 600 mg dose in healthy adult subjects. J Antimicrob Chemother 51:727–30.[Abstract/Free Full Text]

27 Lister PD. (2003) Impact of AUC/MIC ratios on the pharmacodynamics of the des-F(6)-quinolone garenoxacin (BMS-284756) is similar to other fluoroquinolones. J Antimicrob Chemother 51:199–202.[Free Full Text]

28 Nicolau DP, Mattoes HM, Banevicius M, et al. (2003) Pharmacodynamics of a novbel des-F(6)-quinolone BMS-284756 against Streptococcus pneumoniae in the thigh infection model. Antimicrob Agents Chemother 47:1630–5.[Abstract/Free Full Text]

29 Andes D and Craig WA. (2003) Pharmacodynamics of the new des-F(6)-quinolone garenoxacin in a murine thigh infection model. Antimicrob Agents Chemother 47:3935–41.[Abstract/Free Full Text]

30 Azoulay-Dupuis E, Bedos JP, Mohler J, et al. (2004) Activities of garenoxacin against quinolone-resistant Streptococcus pneumoniae in vitro and in a mouse pneumonia model. Antimicrob Agents Chemother 48:765–73.[Abstract/Free Full Text]


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