Comparative Bactericidal Activities of Ciprofloxacin, Clinafloxacin, Grepafloxacin, Levofloxacin, Moxifloxacin, and Trovafloxacin against Streptococcus pneumoniae in a Dynamic In Vitro Model

Abstract

Several new quinolones that exhibit enhanced in vitro activity against Streptococcus pneumoniae have been developed. Using a dynamic in vitro model, we generated time-kill data for ciprofloxacin, clinafloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin against three isolates of quinolone-susceptible S. pneumoniae. Three pharmacokinetic profiles were simulated for each of the study agents (0.1, 1, and 10 times the area under the concentration-time curve [AUC]). Target 24-h AUCs were based upon human pharmacokinetic data resulting from the maximal daily doses of each agent. Ciprofloxacin was the least active agent against all three isolates. With regimens that simulated the human 24-h AUC, ciprofloxacin resulted in an initial, modest decline in the numbers of CFU per milliliter; however, by 48 h the numbers of CFU per milliliter returned to or exceeded the starting inoculum. At the AUC, levofloxacin resulted in variable bacteriostatic and bactericidal activities against the isolates. The remaining agents yielded bactericidal (99.9% reduction) activity by 48 h with regimens that simulated the AUC. At 0.1 time the AUC ciprofloxacin and levofloxacin produced no inhibitory effect, grepafloxacin exhibited bacteriostatic activity, trovafloxacin had mixed static and cidal activities, and clinafloxacin and moxifloxacin caused significant reductions in the numbers of CFU per milliliter by 48 h. All six agents produced cidal activity at 10 times the AUC. In this dynamic in vitro model of infection, the quinolones demonstrated various degrees of activity against S. pneumoniae. The rank order of activity, with respect to bactericidal effect, was ciprofloxacin (least active) Ͻ Ͻ levofloxacin < grepafloxacin, trovafloxacin < clinafloxacin and moxifloxacin (most active). The rank order of the agents with respect to the selection of resistance was ciprofloxacin (most likely) > grepafloxacin, moxifloxacin, and trovafloxacin > levofloxacin > clinafloxacin.The frequency of isolation of penicillin-nonsusceptible strains of Streptococcus pneumoniae increased dramatically during the 1990s (1, 5, 21). Additionally, cross-resistance of these isolates to other classes of antimicrobials such as the cephalosporins, trimethoprim-sulfamethoxazole, macrolides, chloramphenicol, and tetracyclines is extremely common (6). As a result, selection of antimicrobials for the treatment of pneumococcal infections, especially selection of empiric therapy, has become more complicated. The resistance of pneumococci to fluoroquinolones occurs infrequently, even among isolates exhibiting high-level resistance to penicillin (2, 20). Over the past few years, a variety of new fluoroquinolones with enhanced activity against gram-positive pathogens including S. pneumoniae have been developed.Experience with ciprofloxacin in the treatment of pneumococcal infections has left many clinicians wary of using quinolones for the management of pneumococcal respiratory tract infections. These individuals cite reports of treatment failures that have resul...

Activities of Ciprofloxacin and Moxifloxacin against Stenotrophomonas maltophilia and Emergence of Resistant Mutants in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…However, from each parental strain, mutants with a predominant resistance profile were selected, which might reflect strain-specific propensity for the overexpression of different systems; similar resistance profiles were obtained after ciprofloxacin or moxifloxacin exposure. The reduced potential of moxifloxacin to select for bacterial resistance has been assessed for organisms in which high-level quinolone resistance implies target alterations that occur at low frequencies (10 Ϫ7 to 10 Ϫ9 ) and/or multistep mutations (7,21,23,25,29). In S. maltophilia, mutants overproducing their efflux pumps are present at high frequencies (10 Ϫ5 to 10 Ϫ6 ) and exhibit clinically relevant increases in MICs (1,22).…”

In Vitro Pharmacodynamic Evaluation of the Mutant Selection Window Hypothesis Using Four Fluoroquinolones against Staphylococcus aureus

“…Limited observations reported from earlier timekill studies (3, 8, 21-23) precluded delineation of relationships of the area under the concentration-time curve (AUC)/MIC ratio with resistance because the ranges of the simulated AUCto-MIC ratios were too narrow. In fact, the first attempts to relate resistance to the AUC/MIC or peak concentration (C max )/MIC ratio were reported quite recently from studies that declared resistance analysis as a primary goal (1,7,17,18,20,(25)(26)(27)30,33,34; A. MacGowan and K. Bowker, Abstr. 41st Intersci.…”

Moxifloxacina: profilo farmacologico, terapeutico e farmacoeconomico

“…Gli studi effettuati con modelli in vitro hanno dimostrato che la moxifloxacina è dotata di un elevato potere battericida nei confronti dei ceppi sensibili [65][66][67][68][69][70][71][72][73][74] .…”