Antimicrobial activity of moxifloxacin, gatifloxacin and six fluoroquinolones against Streptococcus pneumoniae

Louis Saravolatz*,, Odette Manzor, Christine Check, Joan Pawlak and Bradley Belian

Department of Medicine Research Laboratory, St John Hospital and Medical Center and Wayne State University School of Medicine, Detroit, MI, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
The in vitro and pharmacodynamic effects of moxifloxacin and gatifloxacin against Streptococcus pneumoniae were compared with six other fluoroquinolones. Organisms included penicillin-susceptible (54) and penicillin-non-susceptible (145) isolates from 1998–1999. Moxifloxacin and clinafloxacin demonstrated the greatest in vitro activity, with MIC90s of 0.13 mg/L, followed by trovafloxacin, grepafloxacin > gatifloxacin, sparfloxacin > levofloxacin > ciprofloxacin. There was no difference in fluoroquinolone activity between penicillin-susceptible and -non-susceptible strains. Pharmacodynamic analysis using published pharmacokinetic information indicates that all the agents tested except ciprofloxacin had an AUC/MIC90 > 30, with moxifloxacin having the greatest free-drug availability.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Streptococcus pneumoniae remains a common pathogen causing community-acquired pneumonia, sinusitis, acute exacerbations of chronic bronchitis, acute otitis media and meningitis. Multi-drug resistance has become a global threat to treatment of this organism. A surveillance study in the USA in 1999 indicated that 33% of S. pneumoniae were not fully susceptible to penicillin.1 In the face of the increasing threat of penicillin resistance, new fluoroquinolones with enhanced Gram-positive activity have been promoted for the empirical treatment of respiratory tract infections and the specific treatment of S. pneumoniae. In vitro studies published to date have generally compared new fluoroquinolones with only a small number of agents. This study was undertaken to evaluate the in vitro activity and pharmacodynamics of two recently released fluoroquinolones, moxifloxacin and gatifloxacin, compared with ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, sparfloxacin and trovafloxacin. These antibiotics were tested against 199 clinical isolates of S. pneumoniae from a US regional surveillance study.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Bacterial strains

S. pneumoniae strains (n = 199) isolated during 1998–1999 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 Mueller–Hinton broth supplemented with 2–5% 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 20–24 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


    Results and discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
The susceptibility data determined for each of the antimicrobial agents tested are summarized in the Table. All fluoroquinolones tested, with the exception of ciprofloxacin and levofloxacin, had MIC90s < 1.0 mg/L. Ten isolates (5%) were non-susceptible to ciprofloxacin at a concentration of 4 mg/L. For these isolates there was either no or one two-fold rise in MIC90, which would represent an insignificant change in in vitro activity.

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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Table. Susceptibility of 199 S. pneumoniae clinical isolates and pharmacodynamics for the eight fluoroquinolones tested
 


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Figure. Comparison of the AUC/MIC ratio for fluoroquinolones tested against S. pneumoniae ({blacksquare}, free drug; {square}, bound drug).

 

    Acknowledgments
 
The help of Jane Ambler, PhD, in review of the manuscript and Pat Schultz in the preparation of the manuscript are gratefully acknowledged. This work was supported by grants from Bayer and Bristol-Myers Squibb Pharmaceutical Companies.


    Notes
 
* Corresponding author. Tel: +1-313-343-3362; Fax: +1-313-343-7784; E-mail: louis.saravolatz{at}stjohn.org Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
1 . Thornsberry, C., Critchley, L. A., Mauriz, Y., Kohn, J., Piazzi, G. & Sahm, D. F. (1999). Longitudinal analysis of resistance among Streptococcus pneumoniae isolates from 100 geographically distributed institutions in the United States during the 1997–1998 and l998–1999 respiratory season. In Program and Abstracts of the Thirty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 1999. Abstract 820, p. 109. American Society for Microbiology, Washington, DC.

2 . National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Fourth 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, 19–24.[ISI]

4 . Bergan, T. (1998). Pharmacokinetics of the fluoroquinolones. In The Quinolones, (Andriole, V. T., Ed.), pp. 143–82. 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. 118–21. 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, 1073–81.[Abstract]

7 . Craig, W. A. (1998). Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clinical Infectious Diseases 26, 1–12.[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, 1054–60.[ISI][Medline]

9 . Stein, G. (2000). The methoxyfluoroquinolones: gatifloxacin and moxifloxacin. Infections in Medicine 17, 564–70.[ISI]

Received 25 September 2000; returned 4 December 2000; revised 31 January 2001; accepted 23 February 2001