Impact of plasma protein binding on antimicrobial activity using time-killing curves.

OBJECTIVES Plasma protein binding (PPB) is known to impair the antimicrobial activity of beta-lactams, but its impact on the activity of other classes of antimicrobials such as fluoroquinolones is controversial. This study was undertaken to investigate the effect of PPB on bacterial killing by selected antibiotics and moxifloxacin, which served as a model compound for the class of fluoroquinolones. METHODS Bacterial time-killing curves were employed in the absence and presence of physiological albumin concentrations (40 g/L). Moxifloxacin, ampicillin and oxacillin were investigated. Fosfomycin, a non-protein bound antibiotic was used for comparison. Simulations were carried out by employing concentrations of antibiotics of one-fourth of the minimal inhibitory concentration (MIC), equal to the MIC and four-fold the MIC of one select bacterial strain (Staphylococcus aureus ATCC 29213). To correlate bacterial killing to the extent of PPB, bacterial time-killing curves were plotted using the calculated free and the total drug concentration. RESULTS Bacterial killing by fosfomycin was not affected by the addition of albumin. The antimicrobial activity of oxacillin and ampicillin was reduced in the presence of albumin as expected by the calculation of the free fraction of these antibiotics. Adding albumin to moxifloxacin resulted in a significant decrease in bacterial killing of more than 1 log10 cfu/mL after a period of 8 h when the moxifloxacin concentration was equal to the respective MIC. CONCLUSIONS Our data confirm the view that albumin substantially impairs the antimicrobial activity of antibiotics including moxifloxacin, a member of the class of fluoroquinolones.

[1]  Hartmut Derendorf,et al.  Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Kill Curves versus MIC , 2004, Antimicrobial Agents and Chemotherapy.

[2]  R. Wise,et al.  Effect of protein binding on the in vitro activity and pharmacodynamics of faropenem. , 2002, The Journal of antimicrobial chemotherapy.

[3]  E. Bergogne-Bérézin Clinical Role of Protein Binding of Quinolones , 2002, Clinical pharmacokinetics.

[4]  E. Rubinstein,et al.  The effect of albumin, globulin, pus and dead bacteria in aerobic and anaerobic conditions on the antibacterial activity of moxifloxacin, trovafloxacin and ciprofloxacin against Streptococcus pneumoniae, Staphylococcus aureus and Escherichia coli. , 2000, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[5]  J. Lin,et al.  Dose-dependent plasma clearance of MK-826, a carbapenem antibiotic, arising from concentration-dependent plasma protein binding in rats and monkeys. , 1999, Journal of pharmaceutical sciences.

[6]  R. Wise,et al.  In vitro activity of BAY 12-8039, a new fluoroquinolone , 1997, Antimicrobial agents and chemotherapy.

[7]  J. Klastersky,et al.  Study of the influence of protein binding on serum bactericidal titres and killing rates in volunteers receiving ceftazidime, cefotaxime and ceftriaxone. , 1990, The Journal of hospital infection.

[8]  W. Craig,et al.  Protein binding and its significance in antibacterial therapy. , 1989, Infectious disease clinics of North America.

[9]  W. Craig,et al.  Enhancing effect of serum ultrafiltrate on the activity of cephalosporins against gram-negative bacilli , 1989, Antimicrobial Agents and Chemotherapy.

[10]  R. Jones,et al.  Antimicrobial activity of ceftriaxone, cefotaxime, desacetylcefotaxime, and cefotaxime-desacetylcefotaxime in the presence of human serum , 1987, Antimicrobial Agents and Chemotherapy.

[11]  G. Rolinson,et al.  Effect of protein binding on antibiotic activity in vivo. , 1983, The Journal of antimicrobial chemotherapy.

[12]  K. Stoeckel Pharmacokinetics of Rocephin, a highly active new cephalosporin with an exceptionally long biological half-life. , 1981, Chemotherapy.

[13]  L. Peterson,et al.  Influence of protein binding of antibiotics on serum pharmacokinetics and extravascular penetration: clinically useful concepts. , 1980, Reviews of infectious diseases.

[14]  E. Bruck,et al.  National Committee for Clinical Laboratory Standards. , 1980, Pediatrics.

[15]  U. Ulmann The binding of isoxazolyl penicillins to human serum proteins. , 1977, Arzneimittel-Forschung.

[16]  W. M. Kirby Pharmacokinetics of fosfomycin. , 1977, Chemotherapy.

[17]  W. Craig,et al.  INFLUENCE OF BINDING ON THE PHARMACOLOGIC ACTIVITY OF ANTIBIOTICS , 1973, Annals of the New York Academy of Sciences.

[18]  C. Kunin Clinical pharmacology of the new penicillins: I. The importance of serum protein binding in determining antimicrobial activity and concentration in serum , 1966, Clinical pharmacology and therapeutics.

[19]  Kirby Wm,et al.  A rapid, modified ultrafiltration method for determining serum protein binding and its application to new penicillins. , 1965 .