Department of Medicine Research Laboratory, St John Hospital and Medical Center and Wayne State University School of Medicine, Detroit, MI, USA
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Abstract |
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Introduction |
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Materials and methods |
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S. pneumoniae strains (n = 199) isolated during 19981999 were collected from clinical specimens and stored at 70°C. Only one isolate per patient was included, thus excluding duplication. The isolates were collected from blood (66), respiratory secretions (132) and cerebrospinal fluid (1).
Antimicrobial agents and MICs
Antimicrobial agents as standard powders were provided by the manufacturer and included: ciprofloxacin, moxifloxacin (Bayer Corp., West Haven, CT, USA), clinafloxacin, sparfloxacin (Parke Davis, Ann Arbor, MI, USA), gatifloxacin (Bristol-Myers Squibb, Princeton, NJ, USA), grepafloxacin (Glaxo Wellcome, Research Triangle Park, NC, USA), levofloxacin (Ortho-McNeil, Puritan, NJ, USA) and trovafloxacin (Pfizer, Groton, CT, USA); the powders were used to prepare stock antibiotic dilutions as outlined in the NCCLS standards.2 MICs were determined by broth microdilution assay, using cation adjusted MuellerHinton broth supplemented with 25% lysed horse blood (Cleveland Scientific, Bath, OH, USA). Suspensions were prepared from an 18 h pure culture in saline adjusted to a 0.5 McFarland standard with a final inoculum of 5 x 105 cfu/mL. Microtitre plates were incubated at 35°C for 2024 h in air. The standard quality control strain S. pneumoniae ATCC 49619 was included in each run. Breakpoints used for penicillin susceptibility were divided into three categories according to NCCLS guidelines: penicillin susceptible (PSSP) MIC < 0.06 mg/L; intermediate (PISP) MIC 0.12 1.0 mg/L; and resistant (PRSP) MIC > 2.0 mg/L.2
Pharmacodynamics
Therapeutic indices were calculated by dividing published peak serum concentrations (Cmax) by the appropriate MIC necessary to inhibit 90% of strains tested (MIC90). AUC/ MIC90 ratios were calculated from published pharmacokinetic data as the area under the curve (AUC) divided by the MIC90s determined in the study.35
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Results and discussion |
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When evaluating quinolone activity relative to penicillin susceptibility, isolates categorized into groups as PSSP (54), PISP (78) and PRSP (67) showed no difference for any of the fluoroquinolones tested.
The in vitro activity relative to pharmacokinetics is expressed as pharmacodynamic parameters in the Table and Figure. In terms of Cmax/MIC90, these data show the rank order of activity as: moxifloxacin > clinafloxacin > gatifloxacin > trovafloxacin > grepafloxacin > levofloxacin > ciprofloxacin > sparfloxacin.
The AUC/MIC90 ratios suggest a slightly different rank order in terms of pharmacodynamics, with: moxifloxacin > trovafloxacin > clinafloxacin > gatifloxacin > levofloxacin > grepafloxacin, sparfloxacin > ciprofloxacin. Evaluating agents in terms of free drug and total drug shows a slightly different ranking of the fluoroquinolones tested, gatifloxacin now being the second most active agent (Figure).
When evaluating potency, the newer fluoroquinolones clearly demonstrate superior activity compared with earlier agents such as ciprofloxacin and levofloxacin. The third- and fourth-generation fluoroquinolones both demonstrate improved potency against S. pneumoniae and anaerobes. Earlier work by Forrest et al.6 demonstrated that ciprofloxacin achieved significantly higher microbiological and clinical cure rates when the AUC/MIC90 exceeded 125 compared with patients with AUC/MIC90 of <125. These data were based on the treatment of Gram-negative infections. Although these correlations are based on limited clinical experience, the observations are of interest in trying to provide better predictions of clinical response with the newer fluoroquinolones.
If we adopt an AUC/MIC90 > 30 as necessary in selecting an effective agent, then all of the fluoroquinolones tested except for ciprofloxacin should be effective in respiratory tract infections. However, if a more conservative approach is taken as with Gram-negative organisms where the AUC/MIC90 must exceed 100, then only trovafloxacin and moxifloxacin would meet this criterion.7
As we are becoming more concerned with the emergence of bacterial resistance to new classes of antimicrobial agents, it seems prudent to select the most potent agent in terms of in vitro activity and potential for earliest microbiological eradication. It appears from in vitro pharmacokinetic models that agents with better pharmacodynamic activity (Cmax/MIC90 > 8) may reduce the selection of resistant subpopulations.5,8
In addition to the in vitro activity and potency of the fluoroquinolones evaluated in this study, toxicity must be considered in the selection of any antimicrobial agent. Among the fluoroquinolones tested here, use of three agents (trovafloxacin, clinafloxacin and grepafloxacin) has either been drastically reduced in clinical practice or further development has been halted because of toxicity. Based on the clinical trials experience and the post-marketing surveillance to date, both gatifloxacin and moxifloxacin have demonstrated an acceptable safety profile.9
In summary, whereas all the new fluoroquinolones tested in this study demonstrated enhanced in vitro activity compared with ciprofloxacin and levofloxacin, the new agent with the greatest effect in terms of pharmacodynamics appears to be moxifloxacin.
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Acknowledgments |
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Notes |
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References |
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2 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyFourth Edition: Approved Standard M7-A4. NCCLS, Wayne, PA.
3 . Stein, G. E. (1996). Pharmacokinetics and pharmacodynamics of newer fluoroquinolones. Clinical Infectious Diseases 23, Suppl. 1, 1924.[ISI]
4 . Bergan, T. (1998). Pharmacokinetics of the fluoroquinolones. In The Quinolones, (Andriole, V. T., Ed.), pp. 14382. Academic Press, San Diego, CA.
5 . Turnbridge, J. (1999). Current thinking about pharmacokinetics and pharmacodynamics of antimicrobials. In First International Moxifloxacin Symposium Berlin 1999, (Mandell, L., Ed.), pp. 11821. Sprinzer, Berlin.
6 . Forrest, A., Nix, D. E., Ballow, C. H., Goss, T. F., Birmingham, M. C. & Schentag J. J. (1993). Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrobial Agents and Chemotherapy 37, 107381.[Abstract]
7 . Craig, W. A. (1998). Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clinical Infectious Diseases 26, 112.[ISI][Medline]
8 . Blaser, J., Stone, B. B., Groner, M. C. & Zinner, S. H. (1987). Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance. Antimicrobial Agents and Chemotherapy 31, 105460.[ISI][Medline]
9 . Stein, G. (2000). The methoxyfluoroquinolones: gatifloxacin and moxifloxacin. Infections in Medicine 17, 56470.[ISI]
Received 25 September 2000; returned 4 December 2000; revised 31 January 2001; accepted 23 February 2001