Journal of Antimicrobial Chemotherapy (2000) 46, 725-732
© 2000 The British Society for Antimicrobial Chemotherapy
Comparative pharmacodynamics of moxifloxacin and levofloxacin in an in vitro dynamic model: prediction of the equivalent AUC/MIC breakpoints and equiefficient doses
a Department of Pharmacokinetics, Centre for Science and Technology LekBioTech, 8 Nauchny proezd, Moscow 117246, Russia; b Department of Medicine, Mount Auburn Hospital, Cambridge, MA, USA
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Abstract |
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To demonstrate the impact of the different pharmacokinetics of moxifloxacin and levofloxacin on their antimicrobial effects (AMEs), killing and regrowth kinetics of two clinical isolates of Staphylococcus aureus and one each of Escherichia coli and Klebsiella pneumoniae were studied. With each organism, a series of monoexponential pharmacokinetic profiles of single doses of moxifloxacin (T1/2 = 12.1 h) and levofloxacin (T1/2 = 6.8 h) were simulated. The respective eight-fold ranges of the ratios of area under the concentration–time curve (AUC) to the MIC were 58–475 and 114–934. Species- and strain-independent linear relationships observed between the intensity of AME (IE) and log AUC/MIC were not superimposed for moxifloxacin and levofloxacin (r2 = 0.99 in both cases). The predicted AUC/MIC ratios for moxifloxacin and levofloxacin that might be equivalent to Schentag's AUC/MIC breakpoint for ciprofloxacin (125) were estimated at 80 and 130, respectively. The respective equivalent MIC breakpoints were 0.41 mg/L (for a 400 mg dose of moxifloxacin) and 0.35 mg/L (for a 500 mg dose of levofloxacin). Based on the IE–log AUC/MIC relationships, equiefficient 24 h doses (D24s) of moxifloxacin and levofloxacin were calculated for hypothetical strains of S. aureus, E. coli and K. pneumoniae with MICs equal to the respective MIC50s (weighted geometric means of reported values). To provide an ‘acceptable’ IE = 200 (log cfu/mL)•h, the D24s of moxifloxacin for all three organisms were much lower (150, 30 and 60 mg, respectively) than the clinically proposed 400 mg dose. Although the usual dose of levofloxacin (500 mg) would be in excess for E. coli and K. pneumoniae (D24 = 36 and 220 mg, respectively), it might be insufficient for S. aureus (the estimated D24 = 850 mg). Moreover, to provide the same effect as a 400 mg D24 of moxifloxacin against staphylococci, levofloxacin would have to be given in a 5000 mg D24, which is 10-fold higher than its clinically accepted dose. The described method of generalization of data obtained with specific organisms to other representatives of the same species might be useful to predict the AMEs of new quinolones.
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Introduction |
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Moxifloxacin (BAY 12-8039) has been studied extensively using in vitro dynamic models1–8 but only four studies3,5–7 were comparative. At least three studies3,6,7 exposed differentially susceptible organisms to a given clinical dose and, therefore, to different ratios of the area under the concentration–time curve to the MIC (AUC/MIC). However, the resulting AUC/MIC ranges were only partly overlapping (moxifloxacin versus grepafloxacin,6,7 sparfloxacin3 and levofloxacin3) or did not overlap at all (moxifloxacin versus ciprofloxacin)6. Moreover, in most cases3,7 the simulated AUC/MICs of moxifloxacin were shifted towards higher values than those of the comparators and, therefore, moxifloxacin quite expectedly showed greater effects. Despite these limitations, these data still allow comparison of the quinolones in terms of AUC/MIC–response relationships, but the AUC/MIC analysis of the effect was not performed3,6 or did not show reasonable relationships.7 In three non-comparative studies with moxifloxacin1,4,8 more or less distinct AUC/MIC relationships with the antimicrobial effect were established, but the equiefficient AUC/ MIC ratio and equiefficient dose could not be predicted because of the lack of a comparator.
Such predictions may be based on an analysis of bacterial strain- and species-independent AUC/MIC relationships with the intensity of the antimicrobial effect (IE, the area between control growth and bacterial killing/regrowth curves)9 and the species-specific dose–response relationships as established over a wide range of AUC/MICs.10,11 In the present study, experiments that include the complete regrowth phase were used to compare the antimicrobial effects of moxifloxacin and levofloxacin on Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae in an in vitro dynamic model.
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Materials and methods |
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Antimicrobial agents and bacterial strains
Moxifloxacin and levofloxacin (kindly provided by Bayer Corporation, West Haven, CT, USA and Ortho-McNeill Pharmaceuticals, Raritan, NJ, USA, respectively) were used in the study.
Two clinical isolates of S. aureus with different susceptibilities to moxifloxacin and levofloxacin and one each of E. coli and K. pneumoniae were selected for the study. The true MICs for these organisms determined by multiple serial dilutions as described elsewhere12 were 0.18 mg/L (S. aureus 944), 0.37 mg/L (S. aureus 916), 0.10 mg/L (E. coli 11557) and 0.32 mg/L (K. pneumoniae 56) of moxifloxacin and 0.25, 0.60, 0.20 and 0.20 mg/L, respectively, of levofloxacin. For the prediction of the antimicrobial effects of these quinolones on hypothetical representatives of the above-mentioned species, weighted geometric means of the reported MIC50s of moxifloxacin13–26 and levofloxacin13,18,19,22,24,27–30 were calculated. The respective geometric values of the MIC50 of moxifloxacin for S. aureus, E. coli and K. pneumoniae were 0.15, 0.03 and 0.06 mg/L, and those of levofloxacin were 0.7, 0.03 and 0.18 mg/L, respectively.
In vitro dynamic model and simulated pharmacokinetic profiles
A dynamic model described previously31 was used in the study. The operation procedures, reliability of simulations of the quinolone pharmacokinetic profiles and the high reproducibility of the time–kill curves provided by the model have been reported elsewhere.12
A series of monoexponential profiles that mimic single dose administration of moxifloxacin and levofloxacin were simulated. The simulated half-lives (12.1 h for moxifloxacin and 6.8 h for levofloxacin) represented weighted means of the values reported in humans: 9.1–13.4 h32,33 and 6.0–7.4 h,34–38 respectively. The respective rates of fresh nutrient medium influx into the 60 mL (moxifloxacin) or 40 mL (levofloxacin) central compartments and the antibiotic- and bacteria-containing medium efflux from this compartment were 3.4 and 4.1 mL/h, respectively.
The mean simulated AUC/MIC ratios of moxifloxacin and levofloxacin were similar to those used in our previous studies with trovafloxacin and ciprofloxacin:10 59, 118, 235 and 470, and 115, 230, 460 and 922, respectively. To provide comparable AUC/MIC ratios of moxifloxacin and levofloxacin, the latter of which has a shorter half-life, its peak concentration/MIC ratios were higher than those of the former quinolone (Figure 1
). The overall range of the simulated peak concentration/MIC ratios was 3–27 for moxifloxacin and 12–95 for levofloxacin.
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Determination of the time–kill curves and the antimicrobial effect
In each experiment multiple sampling of medium containing bacteria from the central compartment was performed throughout the observation period. The duration of the experiments was defined in each case as the time until antibiotic-exposed bacteria reached the maximum numbers observed in the absence of antibiotic (
109 cfu/mL). The lower limit of the viable counts was 2 x 102 cfu/mL. The procedure used for quantification of viable counts has been reported elsewhere.12
As described earlier,31 the antimicrobial effect (E) at each time point (t) was expressed by the difference between logarithms of the respective viable counts in the control growth curve (NC) and in the time–kill curve (NA): E(t) = log NC – log NA (Figure 2). Either the area between the log NC–t and log NA–t curves (Figure 2a) or the area under the E–t curve (Figure 2b) describes the total antimicrobial effect as expressed by IE. The upper limit of bacterial numbers, i.e. the cutoff level on the regrowth and control growth curves used to determine the IE was 1011 cfu/mL. In case of lower counts, they were extrapolated to the cutoff level by using a logistic function.
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Relationships between the effect and the AUC/MIC or dose
The IE versus log AUC/MIC data sets obtained with each quinolone against S. aureus, E. coli and K. pneumoniae were fitted by the equation IE = a + b log AUC/MIC (Equation 1).
When predicting the AUC/MIC breakpoints for moxifloxacin and levofloxacin, the reported breakpoint value for ciprofloxacin, 125, which correlated with bacterial eradication in patients with respiratory tract infections,39 was used. This reference breakpoint reflects the critical value of the area under the inhibitory curve (AUIC), which is similar to the AUC/MIC.
To express the antimicrobial effects as a function of quinolone dose (D), the AUC in the linear relationship between IE and log AUC that corresponds to Equation 1 written for a given quinolone–pathogen pair was substituted by D according to the linear equation: AUC = c D (Equation 2). The values of c for moxifloxacin and levofloxacin (0.08 and 0.11, respectively) were calculated on the basis of reported pharmacokinetic data that were obtained with moxifloxacin (Ds from 50 to 800 mg)32,33 and levofloxacin (Ds from 100 to 1000 mg).40
Correlation and regression analyses of the relationship between IE and log AUC/MIC for each quinolone were performed at a level of significance of P = 0.05.
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Results |
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The time courses of viable counts that reflect killing and regrowth of S. aureus, E. coli and K. pneumoniae exposed to monoexponentially decreasing concentrations of moxifloxacin and levofloxacin as well as the respective control growth curves are shown in Figure 3a
–h. As seen in Figure 3, the time–kill curves observed with both quinolones against these three bacterial species yielded similar patterns. At the AUC/MIC ratios studied, regrowth followed a rapid and considerable reduction in bacterial numbers. Steep ascending branches of the E–t curves (Figure 3i–p) reflect the rapid onset of the antimicrobial effect. The maximal Es (Emaxs) produced by both quinolones were greater at higher AUC/MICs, although the AUC/MIC-induced differences of Emaxs were less pronounced than those of the time shift of the regrowth phase (Figure 3a–h) and of the descending branches of the E–t curves (Figure 3i–p). As seen in Figure 3, these shifts were distinctly dependent on the simulated AUC/MIC: the higher the AUC/MIC, the later the regrowth or the disappearance of the antimicrobial effect.
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The respective IEs correlated well with log AUC/MICs for both moxifloxacin and levofloxacin (Figure 4
). The IE–log AUC/MIC plots fitted by Equation 1 were linear, bacterial species and strain independent but quinolone specific (r2 0.99 in both cases). The effects produced by the same AUC/MIC ratio of moxifloxacin were greater than those of levofloxacin. For example, at AUC/MIC = 250, the IE of moxifloxacin was 45% higher than that of levofloxacin.
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, 
), S. aureus 916 (
, 
), E. coli 11557 (
, 
) and K. pneumoniae 56 (
, 
) fitted by Equation 1: a = –415 and b = 323 (moxifloxacin), a = –178 and b = 178 (levofloxacin). Italicized numbers indicate the IEs corresponding to an AUC/MIC of 250. (b) Species-independent IE–log AUC/MIC plots for moxifloxacin and levofloxacin based on data from this study and ciprofloxacin (dashed line) based on reported data.10 The equivalent AUC/MIC breakpoints are indicated by italicized numbers.Based on the IE–log AUC/MIC (Equation 1) and AUC– D (Equation 2) relationships, the respective dose–response curves were constructed for each quinolone against hypothetical representatives of S. aureus, E. coli and K. pneumoniae with MICs equal to the geometric means of MIC50s (Figure 5
). The same antimicrobial effect [IE = 200 (log cfu/mL)•h] against S. aureus might be provided by a much lower absolute dose of moxifloxacin than of levofloxacin: 150 versus 850 mg, respectively (Figure 5c). On the other hand, the D24 of levofloxacin that would reach the same effect as produced by a 400 mg D24 of moxifloxacin, would be 10-fold higher (5000 mg) than the usual clinical dose of levofloxacin. Based on the extrapolated relationship between D and AUC of levofloxacin, the 5000 mg D24 is out of the actual D range in the AUC–D set fitted by Equation 2, and this latter estimate is more conditional than the other values shown in Figure 5. However, it does reflect the order of difference between the quinolone doses that might be necessary to provide the same antimicrobial effect. The doses of moxifloxacin and levofloxacin necessary to efficiently suppress the growth of E. coli (30 and 36 mg, respectively) and K. pneumoniae (60 and 220 mg, respectively) are much lower than 400 mg of moxifloxacin or 500 mg of levofloxacin.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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This comparative pharmacodynamic study provides dose– response relationships and prediction of equiefficient doses of moxifloxacin and levofloxacin for E. coli, K. pneumoniae and S. aureus. These predictions are based on bacterial strain- and species-independent AUC/MIC relationships of the total antimicrobial effect (IE) for the novel quinolone (moxifloxacin) and the comparator (levofloxacin) (r2 0.99 in both cases).
Previously reported AUC/MIC relationships using alternative integral endpoints of moxifloxacin's effect were either weaker (r2 0.51–0.69 with a linear model8 and r2 0.78–0.92 with a sigmoidal model1,4) or uncertain.7 This might have resulted in part from intrinsic limitations inherent in the endpoints, area under bacterial time–kill curve (AUBC)1,4,8 and area above the time–kill curve (AAC)7 as discussed elsewhere.31 For example, unlike IE, AUBC may underestimate the antimicrobial effect at small AUC/MICs and overestimate it at large AUC/MICs when regrowth may not be seen within the observation period. It is not by chance that the correlations reported with AUBC calculated from zero time to 48 h (AUBC0–48) appeared to be stronger (r2 0.92) than those with AUBC calculated from zero time to 24 h (AUBC0–24, r2 0.78)4 because the former endpoint more completely considered the regrowth phase than the latter. Such an analysis is not applicable to the data reported in the other studies cited1,8 where regrowth of four of six strains of S. aureus and ß-haemolytic streptococci8 and eight of nine strains of Haemophilus influenzae and Moraxella catarrhalis1 did not occur during the 48 h observation period.
The usefulness of long-term observations that include the entire regrowth phase rather than only initial bacterial killing in establishing AUC/MIC–response relationships has been demonstrated with trovafloxacin and ciprofloxacin.10,11,31 In this light, the lack of reported correlations between the AUC/MIC ratio of levofloxacin and ciprofloxacin and the time to a 1000-fold reduction in starting inoculum (T99.9%) in experiments with Streptococcus pneumoniae41 and between doses of several quinolones and T99.9% with S. aureus42 might be expected. Similarly, minimal, if any, dose-induced changes could be seen in the rate and extent of initial killing of S. pneumoniae and Enterococcus faecalis exposed to moxifloxacin.2 In another study, although initial killing of K. pneumoniae was similar with moxifloxacin and trovafloxacin, the patterns of bacterial regrowth were quite different.5 Thus, the establishment of AUC/MIC–response relationships may depend dramatically on the experimental design and the method of quantification of the antimicrobial effect.
The IE–log AUC/MIC relationships established here for moxifloxacin and levofloxacin revealed greater antimicrobial effects with moxifloxacin at a given AUC/MIC ratio. Similar differences were reported in our studies with trovafloxacin and ciprofloxacin.10,11 By comparing the IE–log AUC/MIC relationships for moxifloxacin and levofloxacin with that for ciprofloxacin,10 AUC/MIC breakpoints can be predicted that might be equivalent to Schentag's AUC/ MIC = 125 established in a clinical setting.39 As seen in Figure 4b
, to provide an ‘acceptable’ IE = 200 (log cfu/mL)•h that corresponds to the AUC/MIC = 125 for ciprofloxacin, the equivalent AUC/MIC breakpoint for moxifloxacin might be lower, at 80, and that for levofloxacin might be higher, at 130, than the breakpoint value for ciprofloxacin. As follows from Equation 2, a single dose of moxifloxacin (400 mg) provides its AUC of 33 mg•h/L. Its MIC breakpoint is equal to 33/80 = 0.41 mg/L. The respective value for a 500 mg dose of levofloxacin is lower: 46.5/130 = 0.35 mg/L. These MIC breakpoints are higher than the geometric means of MIC50s of moxifloxacin and levofloxacin for E. coli (0.03 mg/L for both agents) and K. pneumoniae (0.06 and 0.18 mg/L, respectively). Most strains of S. aureus will not be covered by levofloxacin (geometric mean of MIC50s 0.7 mg/L) whereas they are more likely to be covered by moxifloxacin (geometric mean of MIC50s 0.15 mg/L).
Although the relevance of these estimates may be verified only in a clinical setting, together with the equiefficient doses, they might be useful for in vitro comparison of relative efficacies of the quinolones. In particular, these data support the important role of the longer half-lives of the newer extended spectrum quinolones whose pharmacokinetic profiles result in a greater antimicrobial effect.10,11
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Acknowledgments |
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This study was supported by a grant from the Bayer Corporation.
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Notes |
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1 Corresponding author. Tel: +7-095-332-3435; Fax: +7-095-332-3335; E-mail: firsov{at}dol.ru
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References |
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1 . Bowker, K. E., Wootton, M., Holt, H. A. & MacGowan, A. P. (1998). In vitro activity of moxifloxacin against Haemophilus influenzae and Moraxella catarrhalis explored using a pharmacodynamic model. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 1998. Poster E-207. American Society for Microbiology, Washington, DC.
2 . Dalhoff, A., Obertegger, S. & Heidtmann, M. (1997). Bactericidal activity of BAY 12-8039 against ß-lactam and vancomycin-resistant staphylococci, pneumococci and enterococci. In Program and Abstracts of the Eighth European Congress of Clinical Microbiology and Infectious Diseases, Lausanne, 1997. Poster P1509. European Society of Clinical Microbiology and Infectious Diseases.
3 . Lister, P. D. & Sanders, C. C. (1998). Pharmacodynamics of moxifloxacin against Streptococcus pneumoniae in an in vitro pharmacokinetic model. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 1998. Poster A-21. American Society for Microbiology, Washington, DC.
4
.
MacGowan, A. P., Bowker, K. E., Wootton, M. & Holt, H. A. (1999). Activity of moxifloxacin, administered once a day, against Streptococcus pneumoniae in an in vitro pharmacodynamic model of infection. Antimicrobial Agents and Chemotherapy 43, 1560–4.
5 . Ullmann, U., Schubert, S. & Dalhoff, A. (1999). Moxifloxacin and trovafloxacin: effect of human serum on bactericidal activity against Klebsiella pneumoniae. In Program and Abstracts of the Ninth European Congress of Clinical Microbiology and Infectious Diseases, Berlin, 1999. Poster P0217. European Society of Clinical Microbiology and Infectious Diseases.
6 . Wiedemann, B. (1998). Pharmacodynamic activity of BAY 12-8039 in an in vitro model against Gram-positive and Gram-negative pathogens. In Program and Abstracts of the Eighth International Congress on Infectious Diseases, Boston, 1998. Poster 12.001. International Society for Infectious Diseases.
7 . Wiedemann, B. (1999). Pharmacodynamic activity of moxifloxacin in an in vitro model against Gram positive and Gram negative pathogens. In Program and Abstracts of the Ninth European Congress of Clinical Microbiology and Infectious Diseases, Berlin, 1999. Poster P0773. European Society of Clinical Microbiology and Infectious Diseases.
8 . Wootton, M., Bowker, K. E., Holt, H. A. & MacGowan, A. P. (1997). Bactericidal activity of moxifloxacin against Staphylococcus aureus and ß-hemolytic straptococci explored using a pharmacodynamic model of infection. In Abstracts of the Thirty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, 1997. Poster A32. American Society for Microbiology, Washington, DC.
9 . Firsov, A. A., Chernykh, V. M. & Navashin, S. M. (1991). Quantitative analysis of antimicrobial effect kinetics in an in vitro dynamic model. Antimicrobial Agents and Chemotherapy 34, 1312–17.
10
.
Firsov, A. A., Vasilov, R. G., Vostrov, S. N., Kononenko, O. V., Lubenko, I. Y. & Zinner, S. H. (1999). Prediction of the antimicrobial effects of trovafloxacin and ciprofloxacin on staphylococci using an in-vitro dynamic model. Journal of Antimicrobial Chemotherapy 43, 483–90.
11
.
Firsov, A. A., Vostrov, S. N., Shevchenko, A. A., Zinner, S. H. & Portnoy, Y. A. (1998). A new approach to in-vitro comparisons of antibiotics in dynamic models: equivalent AUC/MIC breakpoints and equi-efficient doses of trovafloxacin and ciprofloxacin against bacteria of similar susceptibilities. Antimicrobial Agents and Chemotherapy 42, 2841–7.
12
.
Firsov, A. A., Shevchenko, A. A., Vostrov, S. N. & Zinner, S. H. (1998). Inter- and intraquinolone predictors of antimicrobial effect in an in-vitro dynamic model: new insight into a widely used concept. Antimicrobial Agents and Chemotherapy 42, 659–65.
13
.
Bauernfeind, A. (1997). Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin. Journal of Antimicrobial Chemotherapy 40, 639–51.
14 . Blondeau, J. M., Laskowski, R. & Vaughan, D. (1997). In vitro activity of Bay 12-8039, a novel fluoroquinolone antimicrobial agent. In Program and Abstracts of the Thirty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, 1997. Poster F155. American Society for Microbiology, Washington, DC.
15 . Dubois, J. & St-Pierre, C. (1998). Comparative in vitro activity of moxifloxacin against maxillary sinus pathogens. In Program and Abstracts of the Sixth International Symposium on New Quinolones, Denver, 1998. p. 70.
16 . von Eiff, C. & Peters, G. (1998). Comparative in vitro activity of moxifloxacin, trovafloxacin and quinupristin–dalfopristin against staphylococci. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 1998. Poster E-212a. American Society for Microbiology, Washington, DC.
17 . Focht, J. (1998). In vitro activity of moxifloxacin compared with other fluoroquinolones against bacterial strains from upper and lower respiratory tract infections in general practice. In Program and Abstracts of the Eighth International Congress on Infectious Diseases, Boston, 1998. Poster 13.004.
18 . Jones, M. E., Klootwijk, M., Schmitz, F.-J. & Verhoef, J. (1998). Comparative activity of quinolone compounds moxifloxacin, grepafloxacin, trovafloxacin, levofloxacin, sparfloxacin, ofloxacin and the oxazolidinone linezolid against unrelated clinical isolates of ciprofloxacin-resistant and -sensitive Staphylococcus aureus. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 1998. Poster E-212. American Society for Microbiology, Washington, DC.
19 . Kayser, F. N., Santanam, P. & Huf, E. (1998). Activity of moxifloxacin and other fluoroquinolones against speciated staphylococci and potential of staphylococci to develop resistance. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 1998. Poster E-197. American Society for Microbiology, Washington, DC.
20 . Loza, E., Morosini, M. I., Almaras, F. Z., Negri, M. C., Baquero, F. & Spanish Collaborative Group. (1998). Comparative in vitro activity of moxifloxacin against respiratory tract pathogens. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 1998. Abstract E-206. American Society for Microbiology, Washington, DC.
21 . Malathum, K., Singh, K. V. & Murray, B. E. (1998). In vitro activity of moxifloxacin against Gram-positive bacteria. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 1998. Poster E-204. American Society for Microbiology, Washington, DC.
22 . Schmitz, F.-J., Holmann, B., Scheuring, S., Verhoef, J., Fluit, A. C. & Heinz, H. P. (1998). Correlation of MIC values of five fluoroquinolones with mutations within grlA, grlB, gyrA, gyrB in 116 unrelated clinical isolates of Staphylococcus aureus. In Program and Abstracts of the Second European Congress of Chemotherapy and the Seventh Biennial Conference on Antiinfective Agents and Chemotherapy, Hamburg, 1998. Poster T159. European Society for Biomodulation and Chemotherapy.
23 . Schmitz, F. J., Verhoef, J., Fluit, A. C., Heinz, H. P., Hadding, U. & Jones, M. E. (1998). In vitro activity of various antimicrobials against 194 unrelated clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates and stability of MIC values in 125 clonally related clinical MRSA. In Program and Abstracts of the Eighth International Congress on Infectious Diseases, Boston, 1998. Poster 13.007. International Society for Infectious Diseases.
24 . Souli, M., Wennersten, C. B. & Eliopoulos, G. M. (1997). In vitro activity of Bay 12-8039, a novel 8-methoxyquinolone, against species representative of respiratory tract pathogens. In Program and Abstracts of the Thirty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, 1997. Poster F126. American Society for Microbiology, Washington, DC.
25 . Verbist, L. & Verhaegen, J. (1998). In vitro activity of moxifloxacin (Bay 12-8039) against Gram-positive clinical isolates. In Program and Abstracts of the Eighth International Congress on Infectious Diseases, Boston, 1998. Poster 13.015. American Society for Microbiology, Washington, DC.
26 . Wiedemann, B. (1998). Comparative in vitro activity of grepafloxacin and comparators against E. coli, K. pneumoniae, P. aeruginosa, H. influenzae, M. catarrhalis, S. aureus and S. pneumoniae. In Program and Abstracts of the Second European Congress of Chemotherapy and the Seventh Biennial Conference on Antiinfective Agents and Chemotherapy, Hamburg, 1998. Poster T140. European Society for Biomodulation and Chemotherapy.
27 . Ednie, I. M., Jacobs, M. R. & Appelbaum, P. C. (1998). Comparative activity of clinafloxacin against gram-positive and -negative bacteria. In Program and Abstracts of the Sixth International Symposium on New Quinolones, Denver, 1998. p. 142.
28 . Felmingham, D., Robbins, M. J., Mathias, I., Ingley, K., Bhogal, H. & Grüneberg, R. N. (1997). A European multicentre study of the comparative in vitro susceptibility of Gram-positive bacteria to levofloxacin. In Program and Abstracts of the Twentieth International Congress of Chemotherapy, Sydney, 1997. Poster 3276. International Society for Chemotherapy.
29
.
Hoogkamp-Korstanje, J. A. A. (1997). In-vitro activities of ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin, pefloxacin, sparfloxacin and trovafloxacin against Gram-positive and Gram-negative pathogens from respiratory tract infections. Journal of Antimicrobial Chemotherapy 40, 427–31.
30 . Torres-Viera, C., Wennersten, C. B., Moellering, R. C. & Eliopoulos, G. M. (1998). Comparative in vitro activity of gatifloxacin, a new fluoroquinolone antimicrobial, against gram-positive bacteria. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 1998. Poster E-193. American Society for Microbiology, Washington, DC.
31 . Firsov, A. A., Vostrov, S. N., Shevchenko, A. A. & Cornaglia, G. (1997). Parameters of bacterial killing and regrowth kinetics and antimicrobial effect examined in terms of area under the concentration–time curve relationships: action of ciprofloxacin against Escherichia coli in an in-vitro dynamic model. Antimicrobial Agents and Chemotherapy 41, 1281–7.[Abstract]
32
.
Stass, H. H., Dalhoff, A., Kubitza, D. & Schuhly, U. (1998). Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects. Antimicrobial Agents and Chemotherapy 42, 2060–5.
33 . Sullivan, J. T., Woodruff, M., Lettieri, J., Agarwal, V., Krol, G. & Heller, A. H. (1997). Pharmacokinetics (PK) and tolerability of the new methoxyquinolone BAY 12-8039: 10 days treatment at 400 mg daily. In Program and Abstracts of the Eighth European Congress of Clinical Microbiology and Infectious Diseases, Lausanne, 1997. Poster P 389. European Society of Clinical Microbiology and Infectious Diseases.
34 . Chien, S. C., Chow, A. T., Natarajan, J., Williams, R. R., Wong, F., Rogge, M. C. et al. (1997). Absence of age and gender effects on the pharmacokinetics of a single 500-milligram oral dose of levofloxacin in healthy subjects. Antimicrobial Agents and Chemotherapy 41, 1562–5.[Abstract]
35 . Chien, S. C., Chow, A. T., Rogge, M. C., Williams, R. R. & Hendrix, C. W. (1997). Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine. Antimicrobial Agents and Chemotherapy 41, 1765–9.[Abstract]
36 . Chien, S.-C., Rogge, M. C., Gisclon, L. G., Curtin, C., Wong, F., Natarajan, J. et al. (1997). Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses. Antimicrobial Agents and Chemotherapy 41, 2256–60.[Abstract]
37 . Chow, A. T., Chien, S.-C., Fowler, C., Morgan, N., Kojak, C. & Kaminski, S. (1997). Safety and pharmacokinetics of multiple once-daily 750 mg intravenous doses of levofloxacin in healthy volunteers. In Program and Abstracts of the Thirty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, 1997. Abstract A-73, p. 15. American Society for Microbiology, Washington, DC.
38 . Lee, L. J., Hafkin, B., Lee, I. D., Hoh, J. & Dix, R. (1997). Effects of food and sucralfate on a single oral dose of 500 milligrams of levofloxacin in healthy subjects. Antimicrobial Agents and Chemotherapy 41, 2196–200.[Abstract]
39 . Schentag, J. J., Nix, D. E. & Forrest, A. (1993). Pharmacodynamics of the fluoroquinolones. In Quinolone Antimicrobial Agents, 2nd edn, (Hooper, D. C. & Wolfson, J. S., Eds), pp. 259–71. American Society for Microbiology Press, Washington, DC.
40 . Fish, D. N. & Chow, A. T. (1997). The clinical pharmacokinetics of levofloxacin. Clinical Pharmacokinetics 32, 101–19.[Web of Science][Medline]
41 . Wright, D. H., Baeker Hovde, L., Peterson, M. L., Hoang, A. D. & Rotschafer, J. C. (1998). In vitro evalution of pharmacodynamic outcome parameters for fluoroquinolones against Streptococcus pneumoniae. In Program and Abstracts of the Sixth International Symposium on New Quinolones, Denver, 1998. Poster S 15-13.
42
.
Kang, S. L., Rybak, M. J., McGrath, B. J., Kaatz, G. W. & Seo, S. M. (1994). Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model. Antimicrobial Agents and Chemotherapy 38, 2702–9.
Received 28 January 2000; returned 2 May 2000; revised 1 June 2000; accepted 5 August 2000
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