Bristol Centre for Antimicrobial Research and Evaluation, Southmead Health Services NHS Trust and University of Bristol, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK
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Abstract |
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Introduction |
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From these data it can be speculated that, provided quinolones have the same AUC/MIC ratio, they will be equally effective in laboratory models or clinical practice. However, this assumes that all quinolones kill different bacterial species in an equivalent way. This is not the case with pneumococci even if the MICs are similar.14 The purpose of this study was to compare the bactericidal activity of levofloxacin and ciprofloxacin against Pseudomonas aeruginosa by using a sigmoid exposure response model, to determine the 50% AUC/MIC ratios for lethal effect for each agent.
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Materials and methods |
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Data analysis
Time-kill curves were drawn by plotting log cfu/mL against time in hours. The AUBKC for 06.5 h was calculated using the Graph Pad Prism software package (Graph Pad Software Inc., San Diego, CA, USA). The AUBKC was determined by the trapezoid rule.
Drug exposure was calculated by multiplying the quinolone concentrations by 6.5 h or 24 h
then dividing by the MIC for the strain to give an AUC06.5/MIC ratio or
AUC024/MIC ratio. A sigmoidal dose-response with HILLSLOPE 21.0 was
fitted to the data for log AUC06.5/MIC and AUBKC or log AUC024/MIC and log change in viable count at 24 h (24). The minimum and
maximum values, log AUC/MIC producing the 50% response between the maximum and
minimum responses, and r2 were calculated. The percentage of maximal
response produced by an AUC024/MIC of 125 was read off the dose-
response curve for each drug.
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Results |
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As might be expected because of lower ciprofloxacin MIC values, the degree of killing at
equivalent quinolone concentrations in the kill curves was usually significantly superior with
ciprofloxacin than with levofloxacin (Table). With strain 5761, the most
quinolone-susceptible,
this was only apparent at concentrations of 0.5 mg/L as at greater concentrations the strain
was rapidly killed by both drugs. For strain 11683, which was of intermediate susceptibility, and
strain 8545, the least susceptible, both agents were equivalent at low concentration as little
killing occurred with either drug, but at higher concentrations ciprofloxacin was more
bactericidal than levofloxacin as measured by AUBKC (Table). A
dose-response curve was
fitted to the data using AUC06.5/MIC ratio and AUBKC. This allowed the
drugs' bactericidal properties to be compared taking into account ciprofloxacin's
lower MIC. The log AUC06.6/MIC to produce 50% of the maximal
effect was 0.74 ± 0.13 (95% CI, 0.490.99; r2
= 0.9435) for levofloxacin and 0.82 ± 0.06 (95% CI, 0.690.94; r2 = 0.7935) for ciprofloxacin. The maximum AUBKC for the
levofloxacin AUC06.5/MIC responses was 41.3 ± 3.8 (95%
CI, 33.948.8) and the minimum 1.6 ± 1.8 (95% CI, 5.2
to 2.0). Equivalent values for ciprofloxacin were: maximum, 47.4 ± 2.3 (95% CI,
42.851.9); minimum 4.8 ± 1.1 (95% CI, 6.9 to 2.6)
(Figure 1).
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Discussion |
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Our data, in conjunction with many other findings, suggest that in the therapy of P. aeruginosa, ciprofloxacin and levofloxacin will be equally active, provided the drug exposure/MIC ratios are the same. This would seem likely given the pharmacokinetics and in-vitro susceptibilities of these agents.
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Acknowledgments |
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Notes |
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References |
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Received 3 February 1998; returned 23 March 1998; revised 7 April 1998; accepted 7 May 1998