Journal of Antimicrobial Chemotherapy (2001) 48, 821-826
© 2001 The British Society for Antimicrobial Chemotherapy
The pharmacodynamics of gatifloxacin and ciprofloxacin for pneumococci in an in vitro dynamic model: prediction of equiefficient doses
a Department of Medicine, Mount Auburn Hospital, Harvard Medical School, 330 Mount Auburn Street, Cambridge, MA 02138, USA; b Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, Moscow 119992, Russia; c Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908, USA
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Abstract |
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Enhanced activity against Streptococcus pneumoniae is one of the putative advantages of gatifloxacin over older fluoroquinolones such as ciprofloxacin. This study examined ciprofloxacin and gatifloxacin pharmacodynamics against two differentially susceptible clinical isolates of S. pneumoniae (gatifloxacin MIC, 0.125 and 2 mg/L; ciprofloxacin MIC, 1 and 32 mg/L). The pharmacokinetics of gatifloxacin (single dose) and ciprofloxacin (two 12 hourly doses) with half-lives of 6 and 5 h, respectively, were simulated using a two-compartment dynamic model. The AUC/MIC ratios in the peripheral compartments that contain bacterial cultures varied over a four- to five-fold range, from 11 to 48 h with ciprofloxacin and from 15 to 78 h with gatifloxacin. The intensity of the antimicrobial effect (IE) increased with increasing AUC/MIC ratios in a strain-independent fashion, although different relationships of IE to log AUC/MIC were inherent for each drug (r2 0.73 for gatifloxacin and r2 0.94 for ciprofloxacin). Subsequently, the respective dose–response relationships of gatifloxacin and ciprofloxacin for a hypothetical strain of S. pneumoniae with MIC equal to the MIC50 were modelled. Based on these relationships, the equiefficient doses of gatifloxacin and ciprofloxacin were predicted for MIC50S of 0.4 and 1 mg/L, respectively. Gatifloxacin 400 mg was predicted to be equiefficient to ciprofloxacin 1400 mg. To provide the same anti-pneumococcal effect as the usual 1000 mg daily dose of ciprofloxacin, the respective daily dose of gatifloxacin could be as low as 180 mg. This in vitro study demonstrates advantages of gatifloxacin relative to ciprofloxacin in terms of the dose-dependent total antimicrobial effect.
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Introduction |
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Gatifloxacin, an 8-methoxy-fluoroquinolone with enhanced activity against Streptococcus pneumoniae and Staphylococcus aureus, has recently been studied using in vitro pharmacokinetic/pharmacodynamic models.1–4 One such study4 reported anti-pneumococcal effects of gatifloxacin simulating a standard 400 mg dose at a clinically typical half-life (t½) of 6.5 h. Clinically typical half-lives were also simulated in three dose-ranging studies with S. pneumoniae (t½ = 6–8 h)1 and S. aureus, Escherichia coli and Klebsiella pneumoniae (t½ = 7 h)3 over an eight-fold range of the area under the concentration–time curve (AUC) to MIC ratio. In another study with S. pneumoniae (t½ 3–24 h),2 both AUC/MIC and t½ of gatifloxacin varied simultaneously, making clinically reliable predictions impossible. Also, the predictive value of three of these studies1,2,4 was seriously limited by the lack of both data quantification and use of a comparative agent; the findings obtained with levofloxacin at only one AUC/MIC ratio2 did not allow a comprehensive comparison of the fluoroquinolones. These limitations precluded quantitative predictions of the dose of gatifloxacin that might be equiefficient to a clinically accepted dose of an older fluoroquinolone. However, these predictions are useful in antibiotic comparisons and were used recently in a comparative study with gatifloxacin and ciprofloxacin based on the AUC/MIC relationships of the total antimicrobial effect.3 A similar methodology was used in the present study to compare gatifloxacin and ciprofloxacin with regard to anti-pneumococcal effects over a wide range of AUC/ MIC ratios.
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Materials and methods |
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Antimicrobial agents and bacterial strains
Gatifloxacin lactate and ciprofloxacin hydrochloride were kindly provided by Bristol-Myers Squibb (New Brunswick, NJ, USA) and Bayer Corporation (West Haven, CT, USA), respectively. Two clinical isolates of S. pneumoniae, a relatively more susceptible S. pneumoniae 6691 and a less susceptible S. pneumoniae 18032 were selected for the study. The MICs for S. pneumoniae 6691 and 18032 determined by broth microdilution were 0.125 and 2 mg/L, respectively, of gatifloxacin, and 1 and 32 mg/L, respectively, of ciprofloxacin.
In vitro dynamic model and simulated pharmacokinetic profiles
The in vitro dynamic model used in this study has been described previously in detail.5 Briefly, this two-compartment model consists of a central compartment and six bioreactors, artificial capillary chambers (Unisyn Fibertech Corporation, San Diego, CA, USA) connected in series, which model the peripheral compartments. For all experiments the bacterial inoculum was prepared from frozen inocula by thawing, diluting with an equal part of fresh Mueller–Hinton broth (MHB) supplemented with lysed horse blood (LHB; 2% v/v) and incubating for 90 min at 37°C to bring the organisms into growth phase. This mixture was then inoculated into each peripheral compartment, which also contained MHB–LHB-2% via an entry port and incubated until a density of c. 106 cfu/mL was achieved, at which time the antibiotic was introduced into the central compartment (time zero). Antibiotic-free, sterile MHB with 10% pooled horse serum was infused and eluted at flow rates selected to mimic t½ values of 6.5 h (gatifloxacin) and 4.5 h (ciprofloxacin), typical of those reported in humans: 6.0–8.4 h6–8 and 3.2–5.0 h,9–11 respectively. Control experiments without antimicrobial agent were performed with each isolate to characterize growth kinetics. All model experiments were performed in triplicate.
A series of monoexponential profiles that mimic single dose administration of gatifloxacin and two 12 hourly doses of ciprofloxacin were simulated. At the end of a 60 min infusion, the drug concentration was analogous to the peak concentrations reached after oral administration. The AUC/MIC ratios and the respective AUCs simulated in the central compartment of the model are presented in the Table
. As the antimicrobial effect depends on quinolone concentration in peripheral compartments (where the organisms contact the antibiotic), peripheral compartments were sampled for 48 h to determine quinolone concentrations by bioassay using well plates seeded with E. coli ATCC 25922 for ciprofloxacin and Bacillus subtilis ATCC 6633 spore suspension for gatifloxacin. The overall range of the AUC/MIC ratios that reflected different doses was 15–78 h for gatifloxacin and 11–48 h for ciprofloxacin. Typical pharmacokinetic profiles observed in the peripheral compartments at comparable AUC/MIC ratios are shown in Figure 1.
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) and ciprofloxacin (
) in the peripheral compartments at comparable AUC/MIC ratios of 40 and 48 h, respectively.Quantification of the time–kill curves and antimicrobial effect
In each experiment the peripheral compartments were sampled for 48 h to determine bacterial counts. The numbers of surviving organisms were determined by serial dilution of sample in cold sterile saline and inoculation of 20 µL in triplicate on to Mueller–Hinton agar supplemented with 5% sheep blood (MHA–5% SB). Small numbers of bacteria were counted by placing 100 µL of sample into 10 mL of cold sterile saline and filtering this mixture through a 0.45 µm filter. The filter was then placed on to MHA–5% SB. After overnight incubation at 37°C the resulting bacterial colonies were counted, and the cfu/mL were calculated. Ten cfu/mL was the theoretically achievable limit of detection.
The total antimicrobial effect was expressed as the area between the control growth and the antibiotic-induced time–kill/regrowth curves (IE)12,13 (Figure 2). The cut-off level was chosen as 108 cfu/mL, the lowest level of maximal counts observed with or without antibiotic. To quantify pharmacodynamic data reported in another study,2 the published time–kill curves were scanned and digitalized using Grafula II, v. 1.90 software (WESik Soft Haus, Moscow, Russia). Then, the 24 h areas under the time– kill curves (AUBC) were calculated as described elsewhere.14,15
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Relationships between the effect and the AUC/MIC or dose
The IE versus log AUC/MIC data sets combined for both strains of S. pneumoniae exposed to each quinolone were fitted by the equation
 | (1) |
This equation is specific for a particular quinolone but it is strain independent. However, using equation (1)
, the antimicrobial effect against any bacterial strain with its specific MIC can be predicted. This also applies to a hypothetical strain whose MIC is equal to the MIC50. Placing MIC = MIC50 in equation (1), the respective quinolone- and strain-specific relationship of IE to log AUC may be derived:
 | (2) |
To express the antimicrobial effects as a function of quinolone dose (D), the AUC in the MIC50-specific relationship (2) for a given quinolone was substituted by D according to the polynomial equation
 | (3) |
The values of c, d and e for gatifloxacin (0, 7.0 x 10–2 and 3.6 x 10–5, respectively) and for ciprofloxacin (0.54, 1.26 x 10–2 and 1.6 x 10–5, respectively) were calculated by considering the curvilinear pattern of the AUC versus D plots constructed from pharmacokinetic data on gatifloxacin (AUCs at Ds from 100 to 600 mg)7,8 and ciprofloxacin (AUCs at Ds from 100 to 1000 mg)9 reported in humans.
To predict dose-dependent antimicrobial effects on a hypothetical strain of S. pneumoniae with MICs of gatifloxacin and ciprofloxacin equal to the respective MIC50S, weighted geometric means of MIC50S of gatifloxacin16–20 and ciprofloxacin16–20 reported in studies using the broth dilution method were calculated. The weighted geometric mean of the MIC50 of gatifloxacin for S. pneumoniae was estimated as 0.4 mg/L and that of ciprofloxacin as 1 mg/L.
Correlation and regression analyses of the relationships between IE and log AUC/MIC for each quinolone were performed at a level of significance of P = 0.05. To examine the impact of AUC/MIC ratios and t½ of gatifloxacin on its antimicrobial effect, multiple regression analysis of the reciprocal values of AUBC (1/AUBC) versus the simulated AUC/MIC ratios and t½S was performed based on reported time–kill curves of S. pneumoniae.2
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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The time courses of viable counts that reflect killing and regrowth of S. pneumoniae exposed to gatifloxacin and ciprofloxacin as well as the respective control growth curves (AUC/MIC = D) are shown in Figure 3
. Rapid reduction of initial inocula of S. pneumoniae 6691 was observed at gatifloxacin AUC/MICs of 28–78 h and that of S. pneumoniae 18032 at AUC/MICs of 15–69 h. With ciprofloxacin, noticeable initial killing of the same organisms was observed at AUC/MICs of 22–48 and 20–44 h, respectively.
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As seen in Figure 3
, bacterial regrowth followed the initial killing of bacteria with both quinolones. The regrowth curves were differentially shifted along the time axis: in most experiments, except for those with S. pneumoniae 6691 at gatifloxacin AUC/MIC ratios of 40 and 78 h, delay in regrowth was increased with higher AUC/MIC ratios. The intensity of the antimicrobial effect increased with increasing AUC/MIC ratios in a strain-independent fashion (Figure 4).
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, 
) and 18032 (
, 
): combined data fitted by equation (1)Based on these relationships and on equations (2) and (3)
, the respective dose–response curves were constructed for gatifloxacin and ciprofloxacin with MIC50S of 0.4 and 1 mg/L, respectively (Figure 5). As seen in the figure, the IE–log D plots for gatifloxacin are positioned to the left of those for ciprofloxacin showing that the same antimicrobial effect as ciprofloxacin might be achieved with much lower absolute doses of gatifloxacin. These IE–log D curves allow prediction of the doses of gatifloxacin and ciprofloxacin that may provide the same antimicrobial effect. As seen in Figure 5, gatifloxacin 400 mg is equiefficient to a 2 x 700 mg daily dose of ciprofloxacin (1400 mg). On the other hand, to provide the same anti-pneumococcal effect as the usual 2 x 500 mg dose of ciprofloxacin (1000 mg), the respective dose of gatifloxacin would be as low as 180 mg.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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This comparative study presents AUC/MIC relationships of the total antimicrobial effect as expressed by IE to be bacterial strain independent. These findings are consistent with our earlier findings with S. aureus, E. coli and K. pneumoniae3 and our analysis3 of the relationship of 24 h area between the control growth and time–kill curves (ABBC,21 i.e. IE determined over a fixed time interval) to AUC/MIC (r2 = 0.96) based on reported data with three strains of S. pneumoniae exposed to gatifloxacin.1 Moreover, a similar conclusion might be drawn based on a multiple regression analysis of findings obtained in another study2 that varied both gatifloxacin AUC/MIC and t½ simultaneously. To quantify these reported time–kill curves, the AUBCs were calculated. A statistically significant multiple regression of 1/AUBC versus the simulated AUC/MIC ratios and t½S was established with three strains of S. pneumoniae: 1/AUBC = 0.59 log (AUC/MIC) + 0.41 t½ (r2 = 0.94). This regression suggests that both AUC/MIC ratio and t½ may influence the antimicrobial effect in a strain-independent fashion. The impact of t½ on the pharmacodynamics of other fluoroquinolones was reported in our studies with ciprofloxacin and grepafloxacin.22
For most of the simulated AUC/MIC ratios (20–50 h), the effects of a given AUC/MIC ratio were slightly greater with ciprofloxacin than with gatifloxacin (Figure 4). At first glance, this contrasts with previously reported findings that ciprofloxacin was less efficient than those fluoroquinolones with longer t½ values.3,23–25 This apparent discrepancy may be attributed to the different AUC/MIC ranges used in these different studies (11–48 h with ciprofloxacin and 15–78 h with gatifloxacin versus 60–920 h in the previous studies). The slightly larger IES observed with ciprofloxacin in the present study should not be overinterpreted, because the IE versus AUC/MIC data sets obtained with gatifloxacin and ciprofloxacin could be combined resulting in a correlation coefficient (r2 = 0.76) that is comparable to those for the individual fluoroquinolones (r2 = 0.73–0.94). This is consistent with our recent findings with other quinolones26 that showed no significant differences between the pharmacokinetically differing quinolones, gemifloxacin and ciprofloxacin, when examined at AUC/MICs of <60 h.
Based on the strain-independent patterns of the IE–log AUC/MIC relationships that were established in this study, the respective dose–response curves were derived for a hypothetical strain of S. pneumoniae whose MICs were equal to the MIC50S of the two fluoroquinolones. This allowed the prediction of equiefficient doses of the two drugs. According to our analysis, a 400 mg daily dose of gatifloxacin would be equiefficient to a 1400 mg daily dose of ciprofloxacin (Figure 5).
Overall, this in vitro study demonstrates advantages of gatifloxacin relative to ciprofloxacin in terms of the dose-dependent total antimicrobial effect.
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Acknowledgements |
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This study was supported by a grant from Bristol-Myers Squibb.
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Notes |
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* Corresponding author. Tel: +1-617-499-5421; Fax: +1-617-499-5593; E-mail: szinner{at}caregroup.harvard.edu
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References |
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Received 13 February 2001; returned 4 June 2001; revised 20 July 2001; accepted 29 August 2001
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