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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Introduction |
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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 doseresponse 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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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 moxifloxacin1326 and levofloxacin13,18,19,22,24,2730 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 timekill 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: 9.113.4 h32,33 and 6.07.4 h,3438 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 327 for moxifloxacin and 1295 for levofloxacin.
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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 timekill curve (NA): E(t) = log NC log NA (Figure 2). Either the area between the log NCt and log NAt curves (Figure 2a
) or the area under the Et 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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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 quinolonepathogen 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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Discussion |
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Previously reported AUC/MIC relationships using alternative integral endpoints of moxifloxacin's effect were either weaker (r2 0.510.69 with a linear model8 and r2 0.780.92 with a sigmoidal model1,4) or uncertain.7 This might have resulted in part from intrinsic limitations inherent in the endpoints, area under bacterial timekill curve (AUBC)1,4,8 and area above the timekill 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 (AUBC048) appeared to be stronger (r2 0.92) than those with AUBC calculated from zero time to 24 h (AUBC024, 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/MICresponse 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/MICresponse relationships may depend dramatically on the experimental design and the method of quantification of the antimicrobial effect.
The IElog 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 IElog 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 mgh/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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Notes |
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References |
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Received 28 January 2000; returned 2 May 2000; revised 1 June 2000; accepted 5 August 2000