Pharmacodynamic Activities of Ciprofloxacin and Sparfloxacin in a Murine Pneumococcal Pneumonia Model: Relevance for Drug Efficacy
- Jean-Pierre Bédos1,
- Esther Azoulay-Dupuis2,
- Pierre Moine4,
- Martine Muffat-Joly2,
- Benoit Veber2,
- Jean-Jacques Pocidalo1,2 and
- Eric Vallée3
- 1Clinique de Réanimation des Maladies Infectieuses, Hôpital Bichat-Claude Bernard, Paris, France (J-P.B.), 2Institut National de la Santé et de la Recherche Médicale U13, Hôpital Bichat-Claude Bernard, Paris, France (E. A-D., M. M-J., B.V., J-J. P.), 3Laboratoire de Biologie, Centre Hospitalier Emile-Roux, Eaubonne, France (E.V.) and 4Département d’Anesthésie-Réanimation Chirurgicale, Centre Hospitalier de Bicêtre, Le Kremlin Bicêtre, France (P.M.)
Abstract
We looked for associations between pharmacokinetic (Pk) and pharmacodynamic (Pd) parameters of ciprofloxacin (CPFX) and sparfloxacin (SPFX) and the in vivo efficacy of these antimicrobials in an immunocompetent mouse model of severeStreptococcus pneumoniae pneumonia. Bacterial killing curves recorded in the lungs during the 24 h after single subcutaneous injections of the fluoroquinolones (FQs) in doses ranging from 6.25 to 200 mg/kg were compared with mean Pk/Pd parameters in the serum of the same mice. The impact of the dosing interval on the antimicrobial dose response was evaluated based on the survival of mice treated for 3 days with CPFX (25–200 mg/kg) or SPFX (6.25–50 mg/kg) administered at various intervals from 3 to 24 h. Bacterial killing curves showed that the maximal bacterial decrease achieved in the lungs was correlated, similarly for both FQs, with the area under the curve (AUC) above the minimal inhibitory concentration (MIC) (overall correlation: r = 0.968, P < 10−4). CPX attained higher maximal bactericidal effect values, a steeper killing slope and a shorter time to maximal bactericidal effect in comparison with SPX for the highest doses tested. The lower MIC of SPFX compared with CPFX (0.25 vs. 0.75 μg/ml) and its higher AUC/dose ratio (resulting from a lower serum peak but a longer half-life) translated into a greater area under the bactericidal curve. In the dose fractionation experiments, the Pk/Pd parameter most closely correlated with the survival rate for both FQs was the daily AUC/MIC ratio (r = 0.976, P < 10−4). When the AUC/MIC ratio was greater than 160, the probability of a clinical cure was 100%, independently of the dosage schedule.
Footnotes
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Send reprint requests to: J.P. Bédos, Service de Réanimation des Maladies Infectieuses, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France.
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1 Deceased.
- Abbreviations:
- Sp
- Streptococcus pneumoniae
- FQs
- fluoroquinolones
- SPFX
- sparfloxacin
- CPFX
- ciprofloxacin
- MIC
- minimal inhibitory concentration
- AUC
- area under the curve
- T1/2
- elimination half-life
- ΔtMIC
- duration for which serum drug concentrations exceed the MIC
- AUC/MIC ratio
- AUC relative to the MIC
- AUC>MIC
- AUC above the MIC
- Emax
- maximal bactericidal effect
- AUBC
- area under the bactericidal curve
- CFU
- colony forming units
- Pk
- pharmacokinetic
- Pd
- pharmacodynamic
- CI
- confidence interval
- MBC
- minimal bactericidal concentration
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- Received July 2, 1997.
- Accepted March 5, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
