Efficacy of Garenoxacin in Treatment of Experimental Endocarditis Due to Staphylococcus aureus or Viridans Group Streptococci

Abstract

The activity of garenoxacin was investigated in rats with experimental endocarditis due to staphylococci and viridans group streptococci (VGS). The staphylococci tested comprised one ciprofloxacin-susceptible and methicillin-susceptible Staphylococcus aureus (MSSA) isolate (isolate 1112), one ciprofloxacin-susceptible but methicillin-resistant S. aureus (MRSA) isolate (isolate P8), and one ciprofloxacin-resistant mutant (grlA) of P8 (isolate P8-4). The VGS tested comprised one penicillin-susceptible isolate and one penicillin-resistant isolate (Streptococcus oralis 226 and Streptococcus mitis 531, respectively). To simulate the kinetics of drugs in humans, rats were infused intravenously with garenoxacin every 24 h (peak and trough levels in serum, 6.1 and Gram-positive bacteria are major causes of both communityand hospital-acquired severe infections. Over the years, grampositive pathogens have progressively developed resistance against almost all of the available antibacterial agents. For instance, therapeutic options for methicillin-resistant Staphylococcus aureus (MRSA) are often limited to glycopeptides such as vancomycin or, alternatively, to the novel agents quinupristin-dalfopristin and linezolid (3). However, vancomycinintermediate and highly resistant clinical MRSA isolates have recently been described in several countries (5, 6, 23), jeopardizing the use of glycopeptides. In parallel, viridans group streptococci (VGS), which are the leading cause of infectious endocarditis, are becoming resistant to beta-lactams and numerous other drugs (13). The emergence of bacterial resistance to most classes of antibiotics has stimulated the search for new antimicrobial drugs.Garenoxacin (BMS-284756) is a novel des-fluoro(6)-quinolone that appears to be very active against multiresistant S. aureus strains and penicillin-resistant streptococci (20). Therefore, garenoxacin may be particularly well suited as an agent that targets both Staphylococcus spp. and Streptococcus spp. Furthermore, garenoxacin seems to be active against many quinolone-resistant gram-positive cocci (24).The aims of the experiments described below were to determine both the activity of garenoxacin and the risk of the emergence of resistance in vitro and in a rat model of experimental endocarditis. Rats with catheter-induced aortic vegetations were infected with either ciprofloxacin-susceptible or ciprofloxacin-resistant S. aureus or penicillin-susceptible or penicillin-resistant VGS. Infected rats were treated with (i) garenoxacin; (ii) the control quinolone levofloxacin, a new quinolone recently introduced in the clinical setting; (iii) flucloxacillin or vancomycin, the reference drugs for the treatment of endocarditis due to methicillin-susceptible S. aureus (MSSA) and MRSA, respectively, in humans (31); or (iv) ceftriaxone, a recommended alternative for the treatment of endocarditis due to VGS in humans (31). The rats were treated with the drugs so that the kinetics in the serum of rats simulated those in the serum of humans.

Induction of Virulence Gene Expression in Staphylococcus aureus by Pulmonary Surfactant

“…7). Previous reports suggest that SigB contributes to S. aureus virulence in several infection models (55,56). To our knowledge, however, there are no reports demonstrating that host-derived materials such as pulmonary surfactant induce SigB-mediated virulence gene expression in pathogenic bacteria.…”

Garenoxacin Treatment of Experimental Endocarditis Caused by Viridans Group Streptococci

“…A bactericidal effect was observed with 16 g/ml (i.e., 64 times MIC). Although newer quinolones have been reported to be active in the treatment of endocarditis (11,13,14,21), based on our present and prior studies (22) quinolone activity in viridans group streptococcal endocarditis appears to depend on characteristics of the strain causing the disease beyond MICs. Entenza et al proposed that antimicrobial activity in endocarditis may depend on the ability of the agent to achieve bactericidal concentrations inside vegetations.…”

Successful ceftriaxone therapy of endocarditis due to penicillin non-susceptible viridans streptococci

“…12 Animal models of penicillin non-susceptible viridans streptococci have used organisms that are resistant to both penicillin and ceftriaxone. 13 A recent review of endocarditis caused by penicillin non-susceptible viridans streptococci described combination therapy with penicillin and an aminoglycoside or therapy with vancomycin. 12 Therefore the efficacy of ceftriaxone against penicillin non-susceptible, ceftriaxone susceptible isolates has not been evaluated either clinically or in animal models.…”