Evaluation of activity of temafloxacin against Bacteroides fragilis by an in vitro pharmacodynamic system

Sprandel

et al. 2005

Moxifloxacin has been suggested as an option for monotherapy of intra-abdominal infections. Recent data support the use of a once-daily metronidazole regimen. The purpose of this study was to investigate the activity of levofloxacin (750 mg every 24 h [q24h]) plus metronidazole (1,500 mg q24h) compared with that of moxifloxacin (400 mg q24h) monotherapy in a mixed-infection model. By using an in vitro pharmacodynamic model in duplicate, Escherichia coli and Bacteroides fragilis were exposed to peak concentrations of 8.5 mg of levofloxacin/liter q24h, 32 mg of metronidazole/liter q24h, and 2 mg for moxifloxacin/liter q24h for 24 h. The activities of levofloxacin, metronidazole, moxifloxacin, and levofloxacin plus metronidazole were evaluated against E. coli, B. fragilis, and E. coli plus B. fragilis. The targeted half-lives of levofloxacin, metronidazole, and moxifloxacin were 8, 8, and 12 h, respectively. Time-kill curves were analyzed for time to 3-log killing, slope, and regrowth. Pre-and postexposure MICs were determined. The preexposure levofloxacin, metronidazole, and moxifloxacin MICs for E. coli and B. fragilis were 0.5 and 1, >64 and 0.5, and 1 and 0.25 mg/liter, respectively. Levofloxacin and moxifloxacin achieved a 3-log killing against E. coli and B. fragilis in all experiments, as did metronidazole against B. fragilis. Metronidazole did not decrease the starting inoculum of E. coli. The area under the concentration-time curve/MIC ratios for E. coli and B. fragilis were 171.7 and 85.9, respectively, for levofloxacin and 26 and 103.9, respectively, for moxifloxacin. Levofloxacin plus metronidazole exhibited the fastest rates of killing. The levofloxacin and moxifloxacin MICs for B. fragilis increased 8-to 16-fold after the organism was exposed to moxifloxacin. No other changes in the postexposure MICs were found. Levofloxacin plus metronidazole administered once daily exhibited activity similar to that of moxifloxacin against the mixed E. coli and B. fragilis infection. A once-daily regimen of levofloxacin plus metronidazole looks promising for the treatment of intra-abdominal infections.Intra-abdominal infections include peritonitis, appendicitis, and abscesses, among a wide variety of other infections. These infections are commonly caused by a mixture of aerobic and anaerobic bacteria, which creates an especially problematic situation. Not only do anaerobes act synergistically with facultative bacteria, but facultative organisms also facilitate the infectious process by promoting the growth of anaerobes (4).Escherichia coli and Bacteroides fragilis are the organisms most commonly isolated from intra-abdominal abscesses (12). B. fragilis is known to be the most important anaerobic pathogen but accounts for only 0.5% of the normal colonic flora (4). A capsular polysaccharide, adherence potential, piliation, and toxin production all contribute to the virulence of B. fragilis (4).The polymicrobial nature of intra-abdominal infections requires the use of either dual therapy or broad-spectrum monotherapy. ...

Section: Methodsmentioning

confidence: 99%

Levofloxacin plus Metronidazole Administered Once Daily versus Moxifloxacin Monotherapy against a Mixed Infection of Escherichia coli and Bacteroides fragilis in an In Vitro Pharmacodynamic Model

Hermsen

Sprandel

et al. 2005

“…Concentration-time-kill curve studies were conducted by using a previously described in vitro model (17). Growth control experiments were conducted for each of the two P. aeruginosa isolates.…”

Section: Methodsmentioning

confidence: 99%

Synergistic Activity of Colistin and Ceftazidime against Multiantibiotic-Resistant Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model

Gunderson

Ibrahim

et al. 2003

129

Despite the marketing of a series of new antibiotics for antibiotic-resistant gram-positive bacteria, no new agents for multiple-antibiotic-resistant gram-negative infections will be available for quite some time. Clinicians will need to find more effective ways to utilize available agents. Colistin is an older but novel antibiotic that fell into disfavor with clinicians some time ago yet still retains a very favorable antibacterial spectrum, especially for Pseudomonas and Acinetobacter spp. Time-kill curves for two strains of multiantibiotic-resistant Pseudomonas aeruginosa were generated after exposure to colistin alone or in combination with ceftazidime or ciprofloxacin in an in vitro pharmacodynamic model. MICs of colistin, ceftazidime, ciprofloxacin, piperacillintazobactam, imipenem, and tobramycin were 0.125, >32, >4, >128/4, 16, and >16 mg/liter, respectively. Colistin showed rapid, apparently concentration-dependent bactericidal activity at concentrations between 3 and 200 mg/liter. We were unable to detect increased colistin activity at concentrations above 18 mg/liter due to extremely rapid killing. The combination of colistin and ceftazidime was synergistic (defined as at least a 2-log 10 drop in CFU per milliliter from the count obtained with the more active agent) at 24 h. Adding ciprofloxacin to colistin did not enhance antibiotic activity. These data suggest that the antibacterial effect of colistin combined with ceftazidime can be maximized at a peak concentration of <18 mg/liter.The polypeptide antibiotics of the polymyxin class, including polymyxin E (colistin), were first made available for clinical use in the late 1950s and early 1960s. These agents are rapidly bactericidal against many gram-negative bacteria (13). Colistin is available clinically with sulfomethylated amino groups, thought to minimize pain at injection sites as well as having other side effects (2). Studies have found the sulfomethylated derivates to have one-half to one-eighth the activity of the parent compound (8, 13), though the activity of the derivatives may change with time secondary to in vivo hydrolysis and it is not clear which moiety possesses the majority of clinical activity (1, 2). The MIC of the sulfomethyl colistin at which 90% of isolates are inhibited for 94 Pseudomonas aeruginosa isolates was found to be 4 mg/liter, with a range of 0.5 to 32 mg/liter (4).Perhaps as a result of concerns about toxicity, the parenteral use of colistin has been rather limited. Colistin is thought to be nephro-and neurotoxic, though clinical trials involving this agent have not been in universal agreement on the rate of toxicity. (3, 12). The toxicity of colistin was thought to be dose dependent (9), though recent data from a pharmacokinetic study of colistin in 31 cystic fibrosis patients found no relationship between any adverse effects and concentration in plasma (15).Resistance to beta-lactams, quinolones, and aminoglycosides in P. aeruginosa continues to increase. As no novel agents have been introduced to combat these mult...

“…The IVPDM used in this investigation has been previously described by Zabinski et al (10). Levofloxacin (Ortho-McNeil Pharmaceutical, Raritan, N.J.), trovafloxacin (Pfizer, New York, N.Y.), or moxifloxacin (Bayer, West Haven, Conn.) stock solution was injected into the system as a bolus to attain a desired starting peak concentration.…”

mentioning

confidence: 99%

Comparative Pharmacodynamics of Three Newer Fluoroquinolones versus Six Strains of Staphylococci in an In Vitro Model under Aerobic and Anaerobic Conditions

Wright

Gunderson

et al. 2002

Six strains of staphylococci were exposed to levofloxacin, moxifloxacin, or trovafloxacin in an in vitro pharmacodynamic model under both aerobic and anaerobic conditions. Each agent demonstrated a rapid 3-log 10 kill versus susceptible isolates regardless of condition. Against clinical isolates with reduced susceptibility, regrowth occurred by 24 h and was frequently associated with further increases in MICs.