Parenteral sparfloxacin compared with ceftriaxone in treatment of experimental endocarditis due to penicillin-susceptible and -resistant streptococci

Abstract

A new, investigational, parenteral form of sparfloxacin was compared with ceftriaxone in the treatment of experimental endocarditis caused by either of three penicillin-susceptible streptococci or one penicillinresistant streptococcus. Both drugs have prolonged half-lives in serum, allowing single daily administration to humans. Sparfloxacin had relatively low MICs (0.25 to 0.5 mg/liter) for all four organisms and was also greater than or equal to eight times more effective than the other quinolones against 21 additional streptococcal isolates recovered from patients with bacteremia. Ceftriaxone MICs were 0.032 to 0.064 mg/liter for the penicillin-susceptible strains and 2 mg/liter for the resistant isolate. Both antibiotics resulted in moderate bacterial killing in vitro. Rats with catheter-induced aortic vegetations were inoculated with 107 CFU of the test organisms. Antibiotic treatment was started 48 h later and lasted either 3 or 5 days. The drugs were injected at doses which mimicked the kinetics in human serum produced by one intravenous injection of 400 mg of sparfloxacin (i.e., the daily dose expected to be given to human adults) and 2 g of ceftriaxone. Both antibiotics significantly decreased the bacterial densities in the vegetations. However, sparfloxacin was slower than ceftriaxone in its ability to eradicate valvular infection caused by penicillin-susceptible bacteria. While this difference was quite marked after 3 days of therapy, it tended to vanish when treatment was prolonged to 5 days. In contrast, sparfloxacin was very effective against the penicillin-resistant isolate, an organism against which ceftriaxone therapy failed in vivo. No sparfloxacin-resistant mutant was selected during therapy. Thus, in the present experimental setting, this new, investigational, parenteral form of sparfloxacin was effective against severe infections caused by both penicillin-susceptible and penicillin-resistant streptococci.Streptococci are the most frequent causative agents of native-valve endocarditis (19). Classical treatment of such infection advocates several weeks of treatment with multiple daily injections of penicillin alone or in combination with aminoglycosides (2). Recently, a simplified therapeutic schedule consisting of single daily injections of ceftriaxone (a broad-spectrum cephalosporin which has a prolonged half-life in serum) (17) has been shown to cure successfully penicillinsusceptible streptococcal endocarditis in humans (10, 21). In addition, recent experiments also showed that single daily injections of ceftriaxone combined with netilmicin could cure endocarditis caused by penicillin-resistant streptococci in animals (4). Thus, simplified therapeutic schemes involving only one injection of antibiotics may become available for the treatment of both penicillin-susceptible and -resistant streptococcal endocarditis.However, ceftriaxone therapy may present limitations in the numerous patients who are allergic to 3-lactam antibiotics. In such patients, streptococcal endocarditis is usually trea...

Cefotaxime Acts Synergistically with Levofloxacin in Experimental Meningitis Due to Penicillin-Resistant Pneumococci and Prevents Selection of Levofloxacin-Resistant Mutants In Vitro

“…Large inocula (ca. 10 8 CFU/ml) of either WB4 or KR4 were exposed to stepwise-increasing concentrations of antibiotics (9). Series of tubes containing twofold-increasing concentrations of levofloxacin were incubated with either WB4 or KR4 (ca.…”

Comparative in vitro activities of trovafloxacin (CP-99,219) against 445 gram-positive isolates from patients with endocarditis and those with other bloodstream infections

“…Treatment regimens involving oral administration of quinolones have been used for treatment of experimental enterococcal endocarditis with variable success (24,28,30). Also in an experimental setting, sparfloxacin was found to be an effective drug for the treatment of endocarditis due to penicillin-susceptible as well as penicillin-resistant viridans group streptococci (12). These reports, together with the pre- sented data, suggest the importance of further experimental and clinical evaluation of the efficacy of trovafloxacin in the treatment of bacterial endocarditis and other infections caused by gram-positive microorganisms.…”

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.…”

“…Entenza et al proposed that antimicrobial activity in endocarditis may depend on the ability of the agent to achieve bactericidal concentrations inside vegetations. In their study, sparfloxacin was slower than ceftriaxone to achieve bactericidal concentrations in vegetations, potentially explaining differences between the activity of quinolones and beta-lactams in the 3-day treatment model (11). To the best of our knowledge, cardiac valvular penetration of levofloxacin and garenoxacin has not been defined.…”