Synergy of ciprofloxacin and azlocillin in vitro and in a neutropenic mouse model of infection

The time-kill curve methodology was used to determine the pharmacodynamics of piperacillin, ciprofloxacin, piperacillin-tazobactam and the combinations piperacillin-ciprofloxacin and ciprofloxacin-piperacillin-tazobactam. Kill curve studies were performed for piperacillin, ciprofloxacin, and piperacillin-tazobactam at concentrations of 0.25 to 50 times the MICs for 13 strains of bacteria: four Pseudomonas aeruginosa, three Enterobacter cloacae, three Klebsiella pneumoniae, and three Staphylococcus aureus isolates (tazobactam concentrations of 0.5, 4, and 12 g/ml). By using a sigmoid E max model and nonlinear least squares regression, the 50% lethal concentrations and the maximum lethal rates of each agent were determined for each bacterial strain. For piperacillin-ciprofloxacin and ciprofloxacin-piperacillin-tazobactam, kill curve studies were performed with concentrations obtained by the fractional maximal effect method (R. C. Li, J. J. Schentag, and D. E. Nix, Antimicrob. Agents Chemother. 37:523-531, 1993) and from individual 50% lethal concentrations and maximum lethal rates. Ciprofloxacin-piperacillin-tazobactam was evaluated only against the four P. aeruginosa strains. Interactions between piperacillin and ciprofloxacin were generally additive. At physiologically relevant concentrations of piperacillin and ciprofloxacin, ciprofloxacin had the highest rates of killing against K. pneumoniae. Piperacillin-tazobactam (12 g/ml) had the highest rate of killing against E. cloacae. Piperacillin-ciprofloxacin with relatively higher ciprofloxacin concentrations had the greatest killing rates against S. aureus. This combination had significantly higher killing rates than piperacillin (P < 0.002). For all the bacterial strains tested, killing rates by ciprofloxacin were significantly higher than those by piperacillin (P < 0.001). Piperacillin-tazobactam (4 and 12 g/ml) had significantly higher killing rates than piperacillin alone (P < 0.02 and P < 0.004, respectively). The effect of the combination of piperacillin-ciprofloxacin, in which piperacillin concentrations were relatively higher, was not statistically different from that of piperacillin alone (P > 0.71). The combination of ciprofloxacin-piperacillin-tazobactam achieved greater killing than other combinations or monotherapies against P. aeruginosa. The reduction in the initial inoculum was 1 to 4 logs greater with ciprofloxacin-piperacillin-tazobactam at 4 and 12 g/ml than with any other agent or combination of agents. On the basis of the additive effects prevalently demonstrated in the in vitro study, the combinations piperacillin-ciprofloxacin and piperacillin-tazobactam are rational therapeutic options. Greater killing of P. aeruginosa was demonstrated with ciprofloxacin-piperacillin-tazobactam. Since treatment failure of P. aeruginosa pneumonia is a significant problem, clinical studies are warranted.Many studies have attempted to examine the efficacies of various combinations of antimicrobial agents by a wide range of susceptibility test methods includin...

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

In vitro pharmacodynamics of piperacillin, piperacillin-tazobactam, and ciprofloxacin alone and in combination against Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa

Hyatt

Nix

Stratton

et al. 1995

“…These events indicate a need for experimental animal studies with newer antipseudomonal regimens. Antimicrobial combinations have been proposed as a means of increasing bactericidal activity in vivo, and some data suggest a possible synergy of fluoroquinolones with other antimicrobial agents (5,14,20). Moreover, fosfomycin, a drug with remarkable activity against P. aeruginosa, has shown a synergistic bactericidal effect in vitro against multidrug-resistant P. aeruginosa when combined with ciprofloxacin (12,20).…”

mentioning

confidence: 99%

Comparative efficacies of ciprofloxacin and pefloxacin alone or in combination with fosfomycin in experimental endocarditis induced by multidrug-susceptible and -resistant Pseudomonas aeruginosa

Xiong

Potel

Caillon

et al. 1995

The in vivo efficacy of ciprofloxacin or pefloxacin alone or in combination with fosfomycin was evaluated in experimental aortic valve endocarditis induced in 133 rabbits by a multidrug-susceptible or multidrugresistant strain of Pseudomonas aeruginosa. Therapy was initiated early (12 h after infection), when bacterial counts in aortic valve vegetations were relatively low, or late (48 h after infection), when vegetations contained a larger inoculum. Antibiotics were administered as a continuous 24-h intravenous infusion. Mean steady-state levels of ciprofloxacin (64 mg/kg), pefloxacin (64 mg/kg), and fosfomycin (300 mg/kg) in serum were 2.5, 4.2, and 63.9 mg/liter, respectively. For the multidrug-susceptible strain, all regimens except pefloxacin alone significantly reduced the number of CFU per gram of vegetation versus controls, whether treatment was performed early or late. For the multidrug-resistant strain, none of the regimens showed differences from untreated controls, except ciprofloxacin-fosfomycin, which significantly reduced bacterial counts in vegetations compared with controls when therapy was begun early (4.1 ؎ 1.1 log 10 CFU/g of vegetation; P < 0.001 versus the control). These data suggest that combination of fosfomycin with ciprofloxacin or pefloxacin is more effective than ciprofloxacin or pefloxacin alone for the therapy of severe infections caused by multidrugsusceptible P. aeruginosa.Severe infections caused by Pseudomonas aeruginosa are a major problem in hospitalized patients who often fail to respond to medical therapy alone (2, 23). Fluoroquinolones are frequently used in the treatment of severe gram-negative infectious diseases, and ciprofloxacin and pefloxacin have proved effective against certain P. aeruginosa infections (10). However, clinical failures have occurred because of the development of resistance during therapy (22, 23) and there has also been a worldwide emergence of P. aeruginosa strains resistant to multiple older antimicrobial agents. These events indicate a need for experimental animal studies with newer antipseudomonal regimens. Antimicrobial combinations have been proposed as a means of increasing bactericidal activity in vivo, and some data suggest a possible synergy of fluoroquinolones with other antimicrobial agents (5,14,20). Moreover, fosfomycin, a drug with remarkable activity against P. aeruginosa, has shown a synergistic bactericidal effect in vitro against multidrug-resistant P. aeruginosa when combined with ciprofloxacin (12,20).The present study was designed to evaluate the efficacy of ciprofloxacin or pefloxacin alone versus association with fosfomycin. Experiments were conducted with a rabbit model of aortic valve endocarditis induced by a multidrug-susceptible or multidrug-resistant strain of P. aeruginosa. MATERIALS AND METHODSMicroorganisms. Two clinical strains of P. aeruginosa isolated from the blood of burn unit patients with septicemia were found to be susceptible (PA1) or resistant (PA2) to multiple antibiotics. Both proved resistant to rabbit s...

“…Fluoroquinolones in combination with many 1-lactams or aminoglycosides usually have additive or indifferent effects; occasionally they are synergistic but rarely antagonistic (1,5). Vancomycin used in combination with ciprofloxacin against gram-positive microorganisms had an antagonistic effect (14,16,18).…”

mentioning

confidence: 99%

Increased susceptibility of Pseudomonas aeruginosa to ciprofloxacin in the presence of vancomycin

Day¹,

Marceau-Day²,

Day³

1993

Vancomycin in combination with ciprofloxacin exhibited synergy against 7 of 10 strains of Pseudomonas aeruginosa. MICs for the microbial strains used in this study ranged from 0.0325 to 3.0 micrograms/ml for ciprofloxacin and from 23.5 to > 188 micrograms/ml for vancomycin. Combinations of these antibiotics, tested in a checkerboard pattern, gave fractional inhibitory concentrations of 0.5 or less for 7 of the 10 strains tested.