Ciprofloxacin and rifampin, alone and in combination, for therapy of experimental Staphylococcus aureus endocarditis

Abstract

The therapeutic activities of ciprofloxacin (25 mg/kg every 8 h), rifampin (10 mg/kg every 24 h), ciprofloxacin plus rifampin, and vancomycin (17.5 mg/kg every 6 h) were compared by using the rabbit model of Staphylococcus aureus endocarditis. Animals infected with one of two test strains (SA1199 or SA487) were randomized into treatment groups and received 6 days of therapy. For SA1199, ciprofloxacin plus rifampin was most effective at reducing vegetation bacterial counts. For SA487, ciprofloxacin plus rifampin was as effective as vancomycin but' less effective than ciprofloxacin alone. Resistance to ciprofloxacin at 5-and 10-fold the MIC emerged in the test strain in 82 and 55%, respectively, of rabbits infected with SA1199'and receiving ciprofloxacin monotherapy. The combination of ciprofloxacin and rifampin decreased these frequencies to 60% (P = 0.27) and 10% (P = 0.04). No resistance to ciprofloxacin was found in rabbits infected with SA487. We conclude that ciprofloxacin and ciprofloxacin plus rifampin are as efficacious as vancomycin in this model and that combining rifampin with ciprofloxacin may decrease the frequency at which high-level resistance to ciprofloxacin emerges. However, with respect to improved efficacy, the combination of ciprofloxacin and rifampin is unpredictable and may be detrimental.Ciprofloxacin and rifampin are potent antistaphylococcal antimicrobial agents (3, 4). Unfortunately, a major drawback to the use of rifampin for Staphylococcus aureus infections is that resistance develops rapidly when it is used alone (4). This fact relegates the drug to an adjunctive role in such situations.Previous studies have shown monotherapy with ciprofloxacin to be as efficacious as standard therapeutic regimens in experimental methicillin-susceptible and -resistant S. aureus endocarditis (2,7,8). However, we have shown that resistance to ciprofloxacin can emerge during therapy for such infections (8). Resistance to the drug also has developed during treatment of S. aureus infections in humans (5). The effect of combining ciprofloxacin and rifampin for therapy of systemic S. aureus infections, both with respect to improved efficacy and the emergence of resistance to ciprofloxacin, has not been studied. Therefore, we compared the therapeutic activities of these drugs, alone and in combination, with that of vancomycin by using the rabbit model of S. aureus endocarditis. We also evaluated the effect of combining ciprofloxacin and rifampin on the frequency at which resistance to ciprofloxacin emerged in our test strains during therapy. MATERIALS AND METHODSOrganisms. The strains of S. aureus used (SA1199 and SA487) were methicillin-susceptible bloodstream isolates from patients with endocarditis.In vitro studies. The MICs and MBCs of methicillin, * Corresponding author. vancomycin, ciprofloxacin, and rifampin for test strains were determined by a microtiter method, employing cationsupplemented Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) and an inoculum of 5 x 105 CFU/ml (6). Susceptibilit...

Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model

“…many antibiotics into the infected site and the development of resistance to these agents during therapy. Although fluoroquinolones demonstrated excellent in vitro and in vivo activity against S. aureus initially, use of these agents has fallen out of favor because of reports of the rapid emergence of resistance in methicillin-susceptible and -resistant strains during therapy (3,12,(16)(17)(18). However, these reports of resistance were made primarily on the basis of the use of a specific fluoroquinolone, i.e., ciprofloxacin.…”

“…Resistance to levofloxacin or ofloxacin was not observed with any dosage regimen. Furthermore, resistance to ofloxacin was not detected when the half-life was reduced from 6 to 3 h. Regrowth and stable resistance (65-fold increase in the MIC for MSSA 1199; 16-fold increase in the MIC for MRSA 494) were noted within 24 h of exposure to ciprofloxacin at 200 mg ql2h. Combination therapy with rifampin prevented the emergence of resistance to ciprofloxacin.…”

“…Investigators have demonstrated that the addition of rifampin to other antistaphylococcal agents decreases the emergence of resistance in vitro as well as in the rabbit model of S. aureus endocarditis (16,38). However, the enhanced bactericidal activity against S.…”

“…aureus with the addition of rifampin remains controversial (4,16,31,36,38). The purpose of the investigation described here was to compare the bactericidal activities of and the emergence of resistance to levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against MSSA and MRSA strains.…”

Rifampin Combination Therapy for Nonmycobacterial Infections

“…They both have excellent oral bioavailability and safety, allowing them to be used for prolonged courses of therapy. The quinolone-rifampin combinations that have been studied include ciprofloxacin, perfloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin (18,73,74,106,117,137,279).…”