a Department of Pharmacokinetics, Centre of Science &Technology LekBioTech, 8 Nauchny proezd, Moscow 117246, Russia; b Division of Infectious Diseases, Roger Williams Medical Center, Rhode Island Hospital, Brown University, Providence, RI, USA
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Abstract |
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Introduction |
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A similar approach was applied in the present study to compare the antimicrobial effects of trovafloxacin and ciprofloxacin on Staphylococcus aureus which are more susceptible to trovafloxacin than to ciprofloxacin. 6,7,8,9,11,13 For this reason this study was not designed to propose a specific lower dose of trovafloxacin targeted at S. aureus (which might be insufficient to treat Gram-negative infections). The intention was to establish the quinolone doses (D 223) that provide the same I E (average 223 (log cfu/mL) x h) that was considered acceptable at 209 mg of trovafloxacin or 2 x 500 mg of ciprofloxacin against Gram-negative bacteria. 2 Other objectives included an examination of whether the relationships between I E and log AUC/MIC are bacterial strain-independent (as was shown earlier with Gram-negative strains 14) and the prediction of the AUC/ MIC and MIC breakpoints of trovafloxacin. Since our previous study 14 did not confirm the hypothesis that relationships between the antimicrobial effect and AUC/ MIC were independent on the specific quinolone, 15 the present experiments were designed to provide comparable antimicrobial effects (IEs) rather than the same AUC/ MICs. Therefore, the range of the simulated AUC/MIC ratios for ciprofloxacin was shifted towards higher AUC/ MICs relative to the corresponding range for trovafloxacin.
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Materials and methods |
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Trovafloxacin mesylate and ciprofloxacin lactate powders (kindly provided by Pfizer, Inc. (Groton, CT, USA)and by Bayer Pharmaceuticals (West Haven, CT, USA)) were used in the study. Clinical isolates of S. aureus, one methicillin-susceptible (MSSA, S. aureus 48) and two methicillin- resistant (MRSA, S. aureus 944 and 916) were used in the study. The MICs of trovafloxacin for these organisms at an inoculum size of 10 6 cfu/mL, i.e. 0.03, 0.15 and 0.60 mg/L, respectively, were approximately half the corresponding MICs of ciprofloxacin (0.10, 0.25 and 1.25 mg/L).
In-vitro dynamic model and simulated pharmacokinetic profiles
A previously described dynamic model 1 was used in the study. The operation procedure, 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. 14 A series of monoexponential profiles that mimic single-dose administration of trovafloxacin and twice-daily dosing of ciprofloxacin were simulated. The simulated half-lives (9.25 h for trovafloxacin and 4.0 h for ciprofloxacin) were consistent with values reported in human volunteers: 7.29.9 h 16,17 and 3.25.0 h, 18,19,20 respectively. The four simulated AUC/MIC ratios for trovafloxacin and ciprofloxacin were 58, 116, 233 and 466, and 116, 233, 466 and 932 (mg·h/L)/(mg/L), respectively. With ciprofloxacin, the designed AUC/MICs reflect the sum of two AUC/MICs provided by the two doses of the quinolone administered at 12 h intervals taking into account the residual concentrations at the end of the first interval. The respective range of the simulated peak concentration:MIC ratios for trovafloxacin was 432 and that for ciprofloxacin was 1080.
Quantification of the antimicrobial effect and its AUC/MIC and dose relationships
The procedure for quantifying viable counts and the antimicrobial effect by the I
E parameter
1 has been reported elsewhere.
2,14 The I
E versus log AUC/MIC data sets obtained with each quinolone against S. aureus in
this study and S. aureus, E. coli, K. pneumoniae and P. aeruginos (combined data from this
and a previous study
2) were described by the equation
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To express the antimicrobial effects as a function of quinolone dose (D), AUC in a linear relationship between I E and log AUC that corresponds to equation (1) written for a given quinolone- pathogen pair was substituted by D according to the polynomial equation
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where c, d, and e for trovafloxacin are equal to -0.01, 7.5 x 10 -2 and 9.6 x 10 -5, and those for ciprofloxacin are equal to 0.10, 1.4 x 10 -2 and 7.5 x 10 -6, respectively, as calcu-lated based on the quinolone's s pharmacokinetic data in humans. 16,18
To generalize the results of the comparison of the effects of trovafloxacin and ciprofloxacin in
terms of the I
E-log relationships, such relationships were constructed not only for
the
strains studied but also for hypothetical strains of S. aureus, E. coli, K.
pneumoniae, and P.
aeruginos whose MICs corresponded to reported MIC
50s for these organisms. The MIC
50s of trovafloxacin and ciprofloxacin were calculated as weighted geometric means
of the values reported elsewhere.
6,7,8,9,10,11,12,13 Since the MIC
50s for MRSA reported in one study
8 differed substantially from the estimates reported in five
other studies,
6,7,9,11,13 only MIC
50s for MSSA
8 were considered. The weighted geometric means of the
MIC
50s of trovafloxacin for S. aureus, E. coli, K. pneumoniae
and P. aeruginos
were 0.05, 0.03, 0.09 and 0.72 mg/L and those of ciprofloxacin were 0.52, 0.01, 0.03 and 0.31
mg/L, respectively.
Correlation and regression analyses of the relationships between I E and log AUC/MIC for each quinolone were performed at the level of significance of P = 0.05.
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Results |
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The time courses of killing and regrowth of the three strains of S. aureus exposed to trovafloxacin and ciprofloxacin yielded similar patterns (Figure 1). The regrowth followed a rapid and considerable reduction in bacterial numbers and its appearance was distinctly dependent on the simulated AUC/MIC: the higher the AUC/MIC, the later the regrowth. For all three bacterial strains exposed to trovafloxacin at a given simulated AUC/MIC ratio, bacterial regrowth was observed later than with ciprofloxacin, except at 116 (mg·h/L)/(mg/L).
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The combined data sets for S. aureus (this study) and the three Gram-negative organisms 2 were properly fitted by equation (1) for each quinolone (Figure 2). As seen in the figure, I E correlated well with log AUC/MIC of trovafloxacin and ciprofloxacin: in both cases r2 exceed 0.9. By comparing the I Elog AUC/MIC plots, an equivalent AUC/MIC value of trovafloxacin which corresponds to an AUC/MIC of 125 (mg·h/L)/(mg/L) and gives an I E of 198 (log cfu/mL) x h, was estimated at 71 (mg·h/L)/(mg/L). This estimated value might be proposed as an equivalent AUC/MIC breakpoint that in turn might be used to predict the MIC breakpoint of trovafloxacin. From equation (2), a clinically accepted dose of trovafloxacin, namely 200 mg, would give an AUC of 18.9 mg·h/L. The MIC breakpoint is thus equal to 18.9/71 = 0.27 mg/L. The corresponding value for a ciprofloxacin dose of 2 x 500 mg, estimated using equation (2), is lower: 22/125 = 0.18 mg/L.
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Discussion |
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The findings obtained in this and the previous study 2 with specific bacterial strains may also be used to predict the antimicrobial effects of trovafloxacin and ciprofloxacin on hypothetical strains of S. aureus E. coli, K. pneumoniae and P. aeruginos with MICs equal to the respective reported MIC 50s. Due to the bacterial species- and strain-independent relationships between I E and AUC/MIC, equation (1) may be applied to any strain, including those with MICs equal to MIC 50, MIC 90 or the geometric mean of MICs. For example, when the MIC is equal to MIC 50, equation (1) may be rearranged as follows:
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where á = a-b log MIC 50. By using equation (3) and the estimates of a and b presented in Figure 2, the I E-log AUC plots were reconstructed for trovafloxacin and for ciprofloxacin to account for the MIC 50s specific for each of the four bacterial species. In this case, I E = 198 (log cfu/mL) x h at AUC/MIC = 71 (trovafloxacin) or 125 (ciprofloxacin) (mg·h/L)/(mg/L) was used as a reference level of an ` acceptable' antimicrobial effect. The MIC 50-adjusted plots of dose-dependent I Es for the two quinolones and four bacterial species are shown in Figure 4.
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Such an analysis exposes quinolones to the most rigorous conditions since many clinical isolates may in fact be more susceptible than those with MICs equal to MIC 50s. For example, a ciprofloxacin dose <500 mg (2 x 435 mg) was able to produce an ` acceptable' antimicrobial effect on S. aureus 48 (MIC = 0.1 mg/L), and a 2 x 950 mg dose (which is slightly higher than the maximal clinically used oral dose) was sufficient to provide the effect on S. aureus 944 (MIC = 0.25 mg/L) (Figure 3). Similarly, a 200 mg dose of trovafloxacin simulated in our previous study 2 was not less efficient than a 2 x 500 mg dose of ciprofloxacin against P. aeruginosa with MICs of 0.30 and 0.15 mg/L, respectively, barely two-fold lower than the MIC 50s.
Based on the predicted breakpoint value of AUC/MIC, the respective MIC breakpoint of trovafloxacin was predicted to be 0.27 mg/L. As shown in Figure 5, for trovafloxacin and ciprofloxacin against E. coli and K. pneumoniae, the MIC ranges limited from above by the respective MIC 50s do not cross the predicted breakpoint lines. The MIC ranges for ciprofloxacin against S. aureus and for both trovafloxacin and ciprofloxacin against P. aeruginosa do cross the predicted breakpoint line. This diagram demonstrates possible limitations of the two quinolones when administered at their clinically accepted doses.
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Overall, the data presented support the application of the relationships between the antimicrobial effect expressed by I E and the AUC/MIC to compare antimicrobials. 2 Based on these bacterial species-independent relationships, the findings obtained with specific strains might be generalized to other representatives of the same species to predict the antimicrobial effects against organisms of typical susceptibilities as expressed by MIC 50, MIC 90, etc. The suggested approaches to the prediction of quinolone antimicrobial effects might be applicable to other antibiotic classes.
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Acknowledgments |
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Notes |
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References |
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Received 29 April 1998; returned 17 August 1998; revised 26 October 1998; accepted 7 December 1998